As a catcher, Pignatano played in Major League Baseball during all or part of six seasons (1957–1962) for the Brooklyn / Los Angeles Dodgers (1957–1960), Kansas City Athletics (1961), San Francisco Giants (1962), and New York Mets (1962).

He signed with his hometown Dodgers in 1948, and spent almost seven full seasons, interrupted by two years of military service, in their farm system before three brief auditions with the 1957 big-league team.

[1] On September 24, 1957, Pignatano was behind the plate during the final five innings of the Brooklyn Dodgers' last home game, played at Ebbets Field against the Pittsburgh Pirates.

He relieved starting catcher (and future Baseball Hall of Famer) Roy Campanella in the top of the fifth inning with the Dodgers leading 2–0 and helped guide pitcher Danny McDevitt to a complete game shutout victory.

In the flag-clinching Game 2 of the National League playoff series, Pignatano entered the contest as a pinch runner for Norm Larker in the ninth inning, then took over as catcher in the tenth, replacing Roseboro.

The next hitter, Carl Furillo, delivered the game- and pennant-winning run on an infield hit and an error by Braves' shortstop Félix Mantilla.