BACKGROUND & AIMS: Thiazolidinedione ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), are used to treat diabetes. PPARgamma is highly expressed in the colon, and exposure to thiazolidinediones has been proposed to affect the risk for colorectal neoplasia. In vitro models suggest that thiazolidinediones have antineoplastic effects, whereas in vivo studies have produced mixed results: Some indicate an increased risk for intestinal tumors. This study examined the association between PPARgamma-targeted therapies and the risk of colonic neoplasia in patients with diabetes. METHODS: We conducted 3 retrospective case-control studies nested within the cohort of diabetic patients who were cared for within the Kaiser Permanente of Northern California system from 1994 to 2005. Case subjects were those with colonic neoplasia identified at the time of colonoscopy (study 1), sigmoidoscopy (study 2), or at follow-up lower endoscopy (study 3). Controls had no neoplasia identified at the endoscopic examination. A minimum of 1 year of therapy was used to define medication exposure. RESULTS: Fourteen thousand eighty-six patients were included. Among patients undergoing colonoscopy, there was an inverse association between thiazolidinedione exposure and prevalence of neoplasia (adjusted odd ratio [OR], 0.73; 95% confidence interval [CI], 0.57-0.92); however, this was not evident among patients without anemia (adjusted OR, 0.97; 95% CI, 0.64-1.49). Significant associations between any or long-term thiazolidinedione use and colonic neoplasia were not observed among patients undergoing sigmoidoscopy or serial lower endoscopies. CONCLUSIONS: These results indicate that thiazolidinedione therapy is not associated with an increased risk for colonic neoplasia.