Between 1973 and 1976, he worked as a visiting fellow at the Department of Tumor Immunology of the Chester Beatty Research Institute (now the Institute of Cancer Research) in Belmont, Sutton, England, where he continued the studies of Iwan Robert Evans and Peter Alexander.

In 1979 he was appointed Senior investigator in the Department of Tumor Immunology and Chemotherapy at the Istituto di Ricerche Farmacologiche "Mario Negri" in Milan.

In 1987 he worked at the Laboratory of Molecular Immunoregulation of NIH in Frederick, Maryland, as an Eleanor Roosvelt UICC Scholar.

He became Head of the Department of Immunology and Cell Biology at Istituto di Ricerche Farmacologiche "Mario Negri" in 1996.

Between 2001 and 2014, he also served as Full Professor of General Pathology in the School of Medicine of the State University of Milan.

From the study of the regulation of the cytokines, Mantovani was able to identify the operating principle of the decoy receptor for interleukin - 1.

[11] In 2015 his research, published in the journal Cell,[12] showed that PTX3 gene is capable of curbing cancer by controlling inflammation.