Hayreddin Barbarossa
Kapudan-i Derya of the Ottoman Navy

In 1534, Barbarossa set sail from Constantinople with 80 galleys, and in April, he recaptured Coron, Patras and Lepanto from the Spaniards. In July 1534, he crossed the Strait of Messina and raided the Calabrian coasts, capturing a substantial number of ships around Reggio Calabria as well as the Castle of San Lucido. He later destroyed the port of Cetraro and the ships harbored there.

Also in July 1534, he appeared in Campania and sacked the islands of Capri and Procida before bombarding the ports in the Gulf of Naples, where 7,800 captives were taken. He then appeared in Lazio, shelled Gaeta and in August landed at Villa Santa Lucia, Sperlonga, Fondi, Terracina and Ostia on the River Tiber, causing the church bells in Rome to sound the alarm. In Sperlonga he took 10,000 captives and when he arrived in Fondi the janissaries entered the city through the main gates and completely ransacked the palace of Giulia Gonzaga. He then sacked, torched and destroyed Vallecorsa slaughtering some townspeople and taking others captive. He sailed south, appearing at Ponza, Sicily and Sardinia, before capturing Tunis in August 1534 and sending the Hafsid Sultan Mulay Hassan fleeing.

Charles dispatched an agent to offer Barbarossa "the lordship of North Africa" for his changed loyalty, or if that failed, to assassinate him. However, upon rejecting the offer, Barbarossa decapitated the agent with a scimitar.

Mulei Hassan asked Emperor Charles V for help in recovering his kingdom, and a Spanish-Italian force of 300 galleys and 24,000 soldiers recaptured Tunis as well as Bône and Mahdiya in 1535. Recognizing the futility of armed resistance, Barbarossa had abandoned Tunis well before the arrival of the invaders, sailing away into the Tyrrhenian Sea, where he bombarded ports, landed once again at Capri and reconstructed a fort (which still today carries his name) after largely destroying it during the siege of the island. He then sailed to Algiers, from where he raided the coastal towns of Spain, destroyed the ports of Majorca and Menorca, captured several Spanish and Genoese galleys and liberated their Muslim oar slaves. In September 1535, he repulsed another Spanish attack on Tlemcen.

In 1536, Barbarossa was called back to Constantinople to take command of 200 ships in a naval attack on the Habsburg Kingdom of Naples. In July 1537, he landed at Otranto and captured the city, as well as the Fortress of Castro and the city of Ugento in Apulia.

In August 1537, Lütfi Pasha and Barbarossa led a huge Ottoman force that captured the Aegean and Ionian islands belonging to the Republic of Venice, namely Syros, Aegina, Ios, Paros, Tinos, Karpathos, Kasos, Kythira, and Naxos. In the same year, Barbarossa raided Corfu and obliterated the agricultural cultivations of the island while enslaving nearly all the population of the countryside. However, the Old Fortress of Corfu was well defended by a 4,000-strong Venetian garrison with 700 guns, and when several assaults failed to capture the fortifications, the Turks reluctantly re-embarked and once again raided Calabria. These losses prompted Venice to ask Pope Paul III to organize a " Holy League " against the Ottomans.

In February 1538, Pope Paul III succeeded in assembling a Holy League (composed of the Papacy, Spain, the Holy Roman Empire, the Republic of Venice and the Maltese Knights) against the Ottomans, but Barbarossa's forces led by Sinan Reis defeated its combined fleet, commanded by Andrea Doria, at the Battle of Preveza in September 1538. This victory secured Ottoman dominance over the Mediterranean for the next 33 years, until the Battle of Lepanto in 1571.

In the summer of 1539, Barbarossa captured the islands of Skiathos, Skyros, Andros, and Serifos and recaptured Castelnuovo from the Spanish, who had taken it from the Ottomans after the battle of Preveza. He also captured the nearby Castle of Risan, and with Sinan Reis, later assaulted the Venetian fortress of Cattaro and the Spanish fortress of Santa Veneranda near Pesaro. Barbarossa later took the remaining Christian outposts in the Ionian and Aegean Seas. Venice finally signed a peace treaty with Sultan Suleiman in October 1540, agreeing to recognize the Ottoman territorial gains and to pay 300,000 gold ducats.

In 1540 Barbarossa led a crew of 2,000 men and captured and ransacked the town of Gibraltar. He left Gibraltar after taking 75 prisoners which removed a significant percent of Gibraltar’s population, he ultimately eliminated the town of almost an entire generation of Gibraltarians.

In September 1540, Emperor Charles V contacted Barbarossa and offered him to become his Admiral-in-Chief as well as the ruler of Spain's territories in North Africa, but he refused. Unable to persuade Barbarossa to switch sides, in October 1541, Charles himself laid siege to Algiers, seeking to end the corsair threat to the Spanish domains and Christian shipping in the western Mediterranean. The season was not ideal for such a campaign, and both Andrea Doria, who commanded the fleet, and Hernán Cortés, who had been asked by Charles to participate in the campaign, attempted to change the Emperor's mind but failed.

Eventually, a violent storm disrupted Charles's landing operations. Andrea Doria took his fleet away into open waters to avoid being wrecked on the shore, but much of the Spanish fleet went aground. After some indecisive fighting on land, Charles had to abandon the effort and withdraw his severely battered force.
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