After Louis was back in France he continued to send generous assistance to the Holy Land in terms of men and money. His brother Alphonse began planning a new crusade almost as soon as he returned from Syria, but the popes continued to devote their energy and resources to their bitter struggle against the Hohenstaufens. Frederick had died in 1250, leaving the Regno (the kingdom of Sicily and southern Italy) to King Conrad IV, absent in Germany, and appointing his bastard son Manfred regent of both the Regno and North Italy. Excommunicated by Innocent IV, Conrad died on 21 May 1254. In two years Manfred established his rule over the entire Regno, and in August 1258 he succeeded in having himself crowned King of Sicily in Palermo. By the end of 1261 he was a significant threat to the Papal State. In 1262 and 1263 Pope Urban IV authorised negotiations to transfer the Sicilian crown to Charles of Anjou as a papal fief, a project designated from the start as a crusade, and in May 1264 the papal legate Simon of Brie was sent to France to conclude these negotiations and organise the preaching there. He was granted the power to commute the crusading vows of all those in the kingdom of France and the other lands of his legation on condition they instead participate in Charles of Anjou's Sicilian campaign. Charles was crowned on 6 January 1266 at St Peter's in Rome and immediately set out to conquer his fief from Manfred, whom he defeated and killed at the battle of Benevento in 1266. In 1267–1268 young Conradin, the only surviving legitimate grandson of Frederick II, attempted to regain control of the Regno, but was crushed at the battle of Tagliacozzo on 23 August 1268 and then executed.

This overlapped with the period sometimes referred to as the ‘Great Interregnum’. After William of Holland's death in 1256 until the election of Rudolf of Habsburg in 1273 there was no established Holy Roman Emperor. The electors were unable to agree on a German prince, and the two initial candidates for the imperial crown were Richard of Cornwall, brother of King Henry III of England, and King Alfonso X of Castile.