OBJECTIVES: The 5-alpha-reductase inhibitors (5-ARIs), statins, aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) were previously reported to have protection effect for prostate cancer. The aim of this study was to simultaneously investigate these drug effects on prostate cancer risk among benign prostatic hyperplasia (BPH) patients. METHODS: Newly diagnosed BPH patients (ICD-9-CM code: 185 and A-code: A124) with at least one prescription of BPH medications (5-ARIs, alpha-blockers) were identified from Taiwan Longitudinal Health Insurance Database 2000 in 1998-2008. Drug usages of 5-ARIs, statins, aspirin, traditional NSAIDs (tNSAIDs), and cyclooxygenase-2 (COX-2) selective inhibitors were computed in terms of define daily dose (DDD), and were further categorized into high and lose dose groups by medians. The Cox regression was used to estimate hazard ratios (HRs) for the occurrence of prostate cancer. Additional covariates in the model included age, time-dependent covariates of drug usages and Charlson comorbidity score. RESULTS: There were 758 prostate cancers indicated from the registry dataset for catastrophic illness patients from 41,955 BPH patients. The analysis of all studied drugs showed significant protection HRs from univariate analyses. After adjusting for covariates, the multivariable analysis showed significant protection effects on high dose of 5-ARIs (HR=0.47, 95%CI= 0.26-0.99), on high dose of statins (HR=0.56, 95%CI= 0.38-0.83), on both low and high dose of tNSAIDs (HR=0.42, 95%CI= 0.36-0.50; HR=0.25, 95%CI= 0.20-0.31), and on both low and high dose of aspirin (HR=0.73, 95%CI= 0.60-0.88; HR=0.34, 95%CI= 0.26-0.45). The COX-2 selective inhibitors became not significant. CONCLUSIONS: The 5-ARIs, statins, tNSAIDs, aspirin and COX-2 selective inhibitors have been separately investigated their protection effects on the development of prostate cancer. Our results indicated that the protection effects of 5-ARIs, statins, tNSAIDs and aspirin were independently significant. In addition, the protection effect from COX-2 selective inhibitors was appeared to be confounded by other medication.