Charles of Lorraine, Duke of Mayenne (26 March 1554 – 3 October 1611), or Charles de Guise, was a French nobleman of the house of Guise and a military leader of the Catholic League, which he headed during the French Wars of Religion, following the assassination of his brothers at Blois in 1588. In 1596, when he made peace with Henri of Navarre, the wars were essentially at an end. He was the second son of Francis of Lorraine, Duke of Guise and Anna d'Este, the daughter of Ercole d'Este II, Duke of Ferrara and Renée of France.

Charles was absent from France at the time of the massacre of St Bartholomew, but took part in the siege of La Rochelle in the following year, when he was created duke and peer of France. He went with Henry of Valois, Duke of Anjou (later Henry III of France), on his election as king of Poland, but soon returned to France to become the energetic supporter and lieutenant of his brother, Henry I, Duke of Guise.

In 1577 he gained conspicuous successes over the Huguenot forces in Poitou. As governor of Burgundy he raised his province in the cause of the Catholic League in 1585. The assassination of his brothers at Blois, on 23–24 December 1588, left him at the head of the Catholic party.

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