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Spanish period

The first three Spaniards arrived in the city in May 1533, after the Battle of Cajamarca, collecting for Atahualpa 's Ransom Room. On 15 November 1533 Francisco Pizarro officially arrived in Cusco. "The capital of the Incas... astonished the Spaniards by the beauty of its edifices, the length and regularity of its streets." The great square was surrounded by several palaces, since "each sovereign built a new palace for himself." "The delicacy of the stone work excelled" that of the Spaniards'. The fortress had three parapets and was composed of "heavy masses of rock". "Through the heart of the capital ran a river... faced with stone.... The most sumptuous edifice in Cuzco... was undoubtedly the great temple dedicated to the Sun... studded with gold plates... surrounded by convents and dormitories for the priests.... The palaces were numerous and the troops lost no time in plundering them of their contents, as well as despoiling the religious edifices," including the royal mummies in the Coricancha.

Pizarro ceremoniously gave Manco Inca the Incan fringe as the new Peruvian leader. Pizarro encouraged some of his men to stay and settle in the city, giving out repartimientos, or land grants to do so. Alcaldes were established and regidores on 24 March 1534, which included the brothers Gonzalo Pizarro and Juan Pizarro. Pizarro left a garrison of 90 men and departed for Jauja with Manco Inca.

Pizarro renamed it as the "very noble and great city of Cuzco". Buildings often constructed after the Spanish invasion have a mixture of Spanish influence and Inca indigenous architecture, including the Santa Clara and San Blas neighborhoods. The Spanish destroyed many Inca buildings, temples and palaces. They used the remaining walls as bases for the construction of a new city, and this stone masonry is still visible.

Father Vincente de Valverde became the Bishop of Cusco and built his cathedral facing the plaza. He supported construction of the Dominican Order monastery (Santo Domingo Convent) on the ruins of the Corichanca, House of the Sun, and a convent at the former site of the House of the Virgins of the Sun.

During the Siege of Cuzco of 1536 by Manco Inca Yupanqui, a leader of the Sapa Inca, he took control of the city from the Spanish. Although the siege lasted 10 months, it was ultimately unsuccessful. Manco's forces were able to reclaim the city for only a few days. He eventually retreated to Vilcabamba, the capital of the newly established small Neo-Inca State. There his state survived another 36 years but he was never able to return to Cuzco. Throughout the conflict and years of the Spanish colonization of the Americas, many Incas died of smallpox epidemics, as they had no acquired immunity to a disease by then endemic among Europeans.

Cusco was built on layers of cultures. The Tawantinsuyu (former Inca Empire) was built on Killke structures. The Spanish replaced indigenous temples with Catholic churches, and Inca palaces with mansions for the invaders.

Cusco was the center for the Spanish colonization and spread of Christianity in the Andean world. It became very prosperous thanks to agriculture, cattle raising and mining, as well as its trade with Spain. The Spanish colonists constructed many churches and convents, as well as a cathedral, university and archdiocese.