The authors agree that this surname has as its base the given name Sisto, a variant of Sesto, which continues the late Latin Sixtus and Sistus. A. Bongioanni warns that the equivalence between Sisto and Sesto is doubtful, given that the three popes sanctified with this name were of Greek origin, which makes it probable that the form derives from the Greek Xystos ("polished, smooth") rather than from the Latin numeral sextus ("sixth").

Both authors note that the name was consolidated in Christian circles through the prestige of several popes, saints and martyrs. As to its distribution, it is recorded throughout Italy, with a greater frequency in the south, especially in Apulia, and in the centre of the country. The variant Sisti is documented in the centre-north, while Sist appears in Venezia Giulia.