Objectives: Patients with type 2 diabetes mellitus (T2DM) have a higher incidence of bladder cancer (BC); however, the evidence underlining the association between pioglitazone use and BC risk remains inconclusive. We conducted a systematic review and meta-analysis of observational studies to investigate the effect of pioglitazone on risk of BC in T2DM patients. Methods: We searched all publications regarding risk of BC with pioglitazone use through PubMed, Web of Science and Cochrane library databases from inception to March, 2017. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. Results: Total 15 observational (9 cohort and 6 case-control) studies were meta-analyzed. The pooled results showed a significant association between risk of BC and pioglitazone use (HR 1.20, 95%CI 1.09-1.31; P < 0.0001; I 2 = 4%). In subgroup analysis, cumulative dose of pioglitazone (À and >mg) showed a significant association with risk of BC (HR 1.27; 95%CI 1.05-1.54; P = 0.01; I 2 = 0% and HR 1.68, 95%CI 1.36-2.08; P < 0 I 2 = 0% respectively). In addition, a significant association was seen with risk of BC and pioglitazone treatment duration (12-24 months and >24 months) (HR 1.43; 95%CI 1.19-1.71; P = 0.0001; I 2 = 0% and HR 1.58; 95%CI 1.27-1.97; P < 0.0001; I 2 = 29% respectively). Meta-analysis of pioglitazone vs. rosiglitazone use, showed a significant association (HR 1.34; 95%CI 1.05-1.71; P = 0.02; I 2 = 0%) with BC risk and pioglitazone use. Conclusion: Pioglitazone use is associated with risk of BC in T2DM patients. Risk of bladder cancer appears to be associated with higher dose and longer duration of pioglitazone use.