Domingo Mandrafina's first comic was published in Patoruzito, before he became an assistant to Lito Fernandez in 1971. A year later, he joined the art studios that created the 'Sahos' series, which was published in Billiken. At the same time, Mandrafina made comic adaptations of movies for Columbia publishers and contributed to Top magazine. In 1974, Mandrafina created several comics with scenarists like Saccomano and Robin Wood, including 'Lady Shadow', 'Derek, le Condamné' and 'Saravève'.
Domingo Mandrafina started a longtime collaboration with the scenarist Carlos Trillo in 1979, which resulted in series and comics like 'Ulises Boedo', 'El Pinon Fijo', 'El Husmeante', 'Peter Kampf', 'Cosecha Verde' and the series 'Spaghetti Brothers'. The French publisher Albin Michel published his police series 'La Grande Arnaue' (1998, 1999) and 'Vieilles Canailles' (1999).