Several preclinical and observational studies have shown that anti-diabetic medications (ADMs) can modify the risk of hepatocellular cancer (HCC) in patients with diabetes mellitus (DM). We performed a systematic review and meta-analyses of studies evaluating the effect of metformin, thiazolidinediones (TZDs), sulfonylureas, and/or insulin on the risk of HCC. We conducted a systematic search of Medline, EMBASE, and Web of Science up to August 2012. Studies were included if they (1) evaluated and clearly defined exposure to metformin, TZDs, sulfonylureas, and/or insulin, (2) reported HCC outcomes in patients with DM, and (3) reported relative risks or odds ratio (OR) or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CIs) were estimated using the random-effects model. Ten studies reporting 22,650 cases of HCC in 334,307 patients with type 2 DM were included in the analysis. Meta-analysis of observational studies showed a 50% reduction in HCC incidence with metformin use (n=8 studies; OR 0.50, 95% CI 0.34-0.73), 62% and 161% increase in HCC incidence with sulfonylurea (n=8 studies; OR 1.62, 95% CI 1.16-2.24) or insulin use (n=7; OR 2.61, 95% CI 1.46-4.65), respectively. TZDs did not modify the risk of HCC (n=4; OR 0.54, 95% CI 0.28-1.02). There was considerable heterogeneity across studies, which was partly explained by study setting, location, and whether the studies adjusted for the concomitant use of other ADMs. Post-hoc analysis of randomized controlled trials did not reveal any significant association between ADM use and risk of HCC. ADMs may modify the risk of HCC in patients with DM, especially in the Western population. However, the effect of each individual agent should be interpreted with caution owing to inherent cancer-modifying effect of the comparator group.