The HMGA1 proteins have a critical role in the process of carcinogenesis. They are overexpressed in most human malignant neoplasias, and the inhibition of their expression has been shown to prevent cell transformation and results in malignant cell death. To determine whether HMGA1 proteins are also required for in vivo carcinogenesis, we compared the tumour susceptibility of mice wild-type or knockout for the Hmga1-null allele using a two-stage chemical skin carcinogenesis protocol. Hmga1-/- mice exhibited a decreased number and a delayed onset of skin papillomas in comparison with wild-type mice. Moreover, the progression of skin papillomas to carcinomas was observed in only 5% of Hmga1-/- compared to 18% of wild-type mice. These results suggest a lower susceptibility of Hmga1-/- mice to skin carcinogenesis induced by chemical agents.