Thiazolidinediones (TZD) have been shown to down-regulate prostate-specific antigen (PSA) levels in prostate cancer cell lines and decrease PSA velocity among prostate cancer patients; however, the effect of TZDs on serum PSA levels among men with diabetes at risk for prostate cancer is unknown. We conducted a retrospective cohort study of veterans receiving care for diabetes between 1999 and 2005 to determine if TZD use affects PSA levels in veterans at risk for prostate cancer. Eligible patients were male, >or=45 years old, taking at least one oral antidiabetic medication, and with two or more recorded PSA values. Patients with a prior history of prostate cancer or prostatectomy were excluded. Of the 13,791 patients included in the adjusted analysis, 2,016 (14.6%) were prescribed a TZD. No effect of cumulative TZD dose on change in PSA was detected (P = 0.26). Increased TZD exposure was not associated with a change in PSA, suggesting that TZD treatment for diabetes is unlikely to affect prostate cancer detection.