Introduction: Pioglitazone is a second line treatment of diabetes mellitus with insulin-sensitizing properties. The association of pioglitazone with bladder cancer is controversial. We aimed to summarize the results regarding pioglitazone use and bladder cancer risk Material and Methods: A systematic literature search on the relevant literature on pioglitazone and bladder cancer during the period from January 2008 to December 2018 was carried out, studies on animals and human studies in the MEDLINE web of Science, and Pubmed were included using the keywords pioglitazone, thiazolidinedione, and bladder cancer. Results: Out of 156 articles, 40 manuscripts stands after duplication removal and applying the inclusion and exclusion criteria (three experimental studies, thirteen reviews, and twenty-four cohorts). The results were contradicting across all studies, with some showed the association of pioglitazone with bladder cancer with a cumulative dose of 28gm and two years duration, while others reported no association. Conclusion: The evidence regarding the association between pioglitazone and bladder cancer were mixed and some authors suggested conflicts of interests. Pioglitazone has protective cardiovascular effects especially among patients with