The Santullo Crime Family was an American mafia lead by Frank Santullo active from 1911 to 1975. The family's expertise was with scams, fraud and extortion. The Santullo's were an important shareholder in the gambling industry in Las Venturas in the 1950's, neck to neck with the Costanzo Crime Family.

Frank Santullo organised the family back when it was still a crew working for the Costanzo Crime Family. When an internal struggle caused Santullo, Paul Cuccinello and Joseph Costanzo to drift apart, they set up their own area of operations in Las Venturas. Their rackets were simple bookmaking scams in the start, although when the wellfare of their casino business crew, their income quickly leaped into the millions and the Santullo's became the everyday life for many Venturas citizens.

When a truce was made in 1930 between the three competing mobs, the Santullo's acclaimed the southern part of the strip as their territory, proving to live of poverty quite often, whereas their lower ranks were organised youth gangsters that malformed their group into violence as it progressed and old-dogs were replaced by young blood.

In 1946 the FBI opened an investigation against the Santullo family, trying to drive them out of town together with its sister-groups. The environment became heated. Frank Santullo quickly realised they had to come up with something innovative to stay on top, as the mafia endlessly started to suffer of the authorities meddling in their business. When the Cuccinello's quit on the public gambling business, the Santullo's and Costanzo family were more competitive than ever. The Santullo's knew they had to put a stop to their competition, now that their former third-party that recently retired from the gambling racket had been replaced with a more ferocious enemy; the suits. Frank Santullo decided he would get rid of Joseph Costanzo once and for all, and hired two hitmen to liquidate their family boss.

After Joseph Costanzo had been succesfully killed in 1972, the Santullo's faced the unexpected vengeance of his successor, Benjamin Costanzo, whom put a bounty on the heads of the family's most important figures. A hit-squad quickly picked up on this rumor in 1974, and killed most of its captains, its underboss and Frank Santullo himself in 1975. It was official that the Santullo family was forfeit, when all their chances of retaliation had been made impossible when its remainders decided to retire or join Paul Cuccinello.

The deserters that left the Santullo's oath to work with Cuccinello instead, were murdered by mobsters alligned to the Cuccinello Family and Costanzo Crime Family that flocked to clean up all that was left to settle the deed.