In 1952, DeSpirito began his record-setting year well behind other American jockeys in races won, as he did not get his first win until January 22 at Sunshine Park in Oldsmar, Florida.

That month, he rode in Florida; when the tracks there closed on Sunday, he flew to Cuba and won three races on December 28 at Oriental Park Racetrack in Havana.

On December 30, 1952, he rode his 389th winner at Tropical Park Race Track in Coral Gables, Florida, breaking the record for most wins in a single year set by Walter Miller in 1906.

[9] In 1953, DeSpirito continued his winning ways but was involved in the first of four serious accidents that profoundly affected his career and saw the media dub him the "Hard Luck Kid".

During 1954, DeSpirito battled with riding greats Avelino Gomez and Bill Shoemaker for top jockey honors in the United States and by July 10 had taken over the lead with 176 wins.

He returned to racing in January 1956; in May, he was hurt again in an accident at Laurel Park Racecourse in Maryland and had to undergo surgery to remove a damaged kidney and spleen.

In the 1960 edition, he finished second in a field of six aboard future Canadian Horse Racing Hall of Fame colt Victoria Park.

[17] DeSpirito married Doris De Christoforo in a church ceremony in Revere, Massachusetts, on November 1, 1953; their wedding was attended by Nelson Eddy.