Background : the association between type 2 diabetes mellitus (DM2) and hepatocarcinoma (HCC) has been identified in the last ten years. Methods: to clarify the temporal relationship between DM2 and HCC and the possible effects of antidiabetic therapy on HCC risk, we recruited 465 patients with HCC compared with 490 control subjects without liver diseases and 618 cirrhotic patients. Results: prevalence of DM2 was 31.2% in HCC, 23.3% in cirrhotic and 12.7% in control group. In univariate and multivariate analysis, the odds ratio (OR) for HCC in diabetic patients were respectively 3.12 (CI 2.2-4.4; P <0.001) and 2.2 (CI 1.2-4.4; P= 0.01). OR in univariate analysis were higher in male than in female patients. In 84.9% of the patients DM2 pre-exists the diagnosis of HCC from a mean time of 141.5 months. Moreover, the insulin treatment was more frequent in diabetic HCC patients than controls and we report an OR for HCC of 2.99 (CI 1.34-6.65; P= 0.007) in patients treated with insulin or sulfonylureas, and an OR of 0.33 (CI 0.1-0.7; P= 0.006) in patients treated with metformin.