A sestiere (plural: sestieri) is a subdivision of certain Italian towns and cities. The word is from sesto, or sixth; and is thus used only for towns divided into six districts. The best-known example are the sestieri of Venice, but Ascoli Piceno, Genoa, Milan and Rapallo, for example, were also divided into sestieri. The medieval Lordship of Negroponte, in the island of Euboea, was also at times divided into six distinct rulerships through the arbitration of Venice, which were known as sestieri. The island of Crete, a Venetian colony (the "Kingdom of Candia") since the Fourth Crusade, was also divided into six parts, named after the sestieri of Venice herself, while the capital Candia retained the status of a commune of Venice. Also, the island of Burano north of Venice is subdivided into sestieri.

A variation of the word is occasionally met with; the comune of Leonessa, for example, is divided into sesti or sixths.

Other Italian towns with fewer than six official districts are frequently divided into analogous quartieri (4, whence the English word "quarter" to mean a neighbourhood) or terzieri (3); some towns merely refer to these neighbourhoods by the non-number-specific rioni. Sestieri, quartieri, terzieri, rioni, and their analogues are usually no longer administrative divisions of these towns, but historical and traditional communities, most often seen in their sharpest relief in the town's annual palio.