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The first automobile bearing this marque featured a four-cylinder engine with an output of 24 hp. The car, driven by Vincenzo Fraschini, appeared in several races. In 1905, Isotta-Fraschini gained notoriety in the Coppa Florio, where they entered aTipo D with an enormous 17.2-litre (1,050 cu in) 100 horsepower (75 kW) engine. For a short time in 1907, Isotta-Fraschini merged with Lorraine-Dietrich. The firm started out making race cars using this same 100 horsepower (75 kW) engine, establishing the company's reputation and gave its name considerable cachet. It was also one of the first cars with four-wheel brakes, following their invention by the Arrol-Johnson Company of Scotland in 1909.[1] They were also among the early pioneers of OHC, with an engine designed by Giustino Cattaneo.[2] In 1924, the Type D was one of the first European cars with an eight-cylinder engine (following the first production straight eight by Rolls-Royce in 1905).

With the growth of the wealthy middle class in North America in the 1920s, Isotta Fraschini marketed deluxe limousines to the new American aristocracy. Early film stars Clara Bow and Rodolfo Valentino drove Isotta Fraschinis. A 1929 Tipo 8A Castagna Transformable is featured in the famous 1950's film Sunset Boulevard and another appears in the 1934 film, "Death Takes a Holiday" with Fredric March.

Seriously affected by the economic crisis of the 1930s and by the disruptions of World War II, Isotta-Fraschini stopped making cars after the war (1949). Only five of the last model, the Monterosa, were produced. The plants were converted to produce marine engines.

The company was still left on company register and in 1955 it was merged with engine manufacturer Breda Motori and named as F.A. Isotta Fraschini e Motori Breda. The company started to built trolley buses again and in 1960s was built new diesel engine factory to Bari. In the 1980s the company was renamed as Isotta Fraschini Motori SpA and it came part of Fincantieri group, it has administrative headquarter in the old factory in Bari.

After 100 years of foundation of the fabulous automotive corporation, on 2002, in Milan, a shiny brand-new company – as well named Isotta Fraschini Milano – does appear through a range of must-have fineness. Luxury goods, handmade, and strictly in Italy.