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Queen of France

Henry allowed Catherine almost no political influence as queen. Although she sometimes acted as regent during his absences from France, her formal powers were strictly nominal. Henry even gave the Château of Chenonceau, which Catherine had wanted for herself, to his mistress Diane de Poitiers instead, who took her place at the center of power, dispensing patronage and accepting favors. The imperial ambassador reported that in the presence of guests, Henry would sit on Diane's lap and play the guitar, chat about politics, or fondle her breasts. Diane never regarded Catherine as a threat. She even encouraged the king to spend more time with Catherine and sire more children.

In 1556, Catherine nearly died giving birth to twin daughters, Jeanne and Victoire. Surgeons saved her life by breaking the legs of Jeanne, who died in her womb. The surviving daughter, Victoire, died seven weeks later. Because their birth very nearly cost Catherine her life, the king's physician advised the king that there should be no more children; therefore, Henry II stopped visiting his wife's bedroom and spent all his time with his longtime mistress, Diane de Poitiers. Catherine had no more children.

Henry's reign enabled the rise of the Guise brothers, Charles, who became a cardinal, and Henry's boyhood friend Francis, both of whom became Duke of Guise. Their sister Mary of Guise had married James V of Scotland in 1538 and was the mother of Mary, Queen of Scots. At the age of five and a half, Mary was brought to the French court, where she was promised to the Dauphin, Francis. Catherine brought her up with her own children at the French court, while Mary of Guise governed Scotland as her daughter's regent.

On 3–4 April 1559, Henry signed the Peace of Cateau-Cambrésis with the Holy Roman Empire and England, ending a long period of Italian Wars. The treaty was sealed by the betrothal of Catherine's teenage daughter Elisabeth, aged 13, to Philip II of Spain. Their proxy wedding was celebrated in Paris on 22 June 1559. As part of the celebrations, a jousting tournament was held on 30 June 1559.

King Henry took part in the jousting, sporting Diane's black-and-white colours. He defeated the dukes of Guise and Nemours, but the young Gabriel, comte de Montgomery, knocked him half out of the saddle. Henry insisted on riding against Montgomery again, and this time, Montgomery's lance shattered in the king's face. Henry reeled out of the clash, his face pouring blood, with splinters "of a good bigness" sticking out of his eye and head. Catherine, Diane, and Prince Francis all fainted. Henry was carried to the Château de Tournelles, where five splinters of wood were extracted from his head, one of which had pierced his eye and brain. Catherine stayed by his bedside, but Diane kept away, "for fear", in the words of a chronicler, "of being expelled by the Queen". For the next ten days, Henry's state fluctuated. At times he even felt well enough to dictate letters and listen to music. Slowly, however, he lost his sight, speech, and reason, and on 10 July 1559, he died, aged 40. From that day, Catherine took a broken lance as her emblem, inscribed with the words " lacrymae hinc, hinc dolor " ("from this come my tears and my pain"), and wore black mourning in memory of Henry.