The city's foundation as a fortified settlement dates from the Saracens' rule of Sicily. Like many Arab towns, Caltanissetta's name shares the Arabic prefix kal indicating that it was indeed a fortified, or castled, city. In this case, it derived its name from Kalat Nisa or "the castle of women," as it is said that the Emir of Palermo kept his women here. Considerably broadened in Norman times, this fortress, the Castello Pietrarossa, is visible on the edge of the city, although only part of a tower and some walls remain. The castle was sacked during the War of the Vespers but the looters were subsequently pardoned by the new sovereign, Peter of Aragon.

Caltanissetta has a large 17th-century Duomo built on the site of a previous medieval church, and a handful of late-medieval churches in the old part of town, though most of the latter, having been extensively modified in successive centuries, reflect little of their origins. There are also some exquisite baroque palaces, particularly Palazzo Moncada on Corso Vittorio Emanuele and the Palazzo Vescovile in Viale Regina Margherita.

The exquisite Abbazia dello Spirito Santo, lying roughly 4kms/2.4 miles from the center of town, is a Norman abbey built upon Saracen fortifications, the purpose of which was to create a house of worship for the landworkers, as the Normans continued their quest to re-Christianize Sicily.

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