OBJECTIVES: Breast cancer outcomes have improved with recent advancements in diagnosis and treatment. Interest in breast cancer prevention is growing, and more clinical evidence is needed regarding the effects of preventive therapy, alone or in combination, on breast cancer. METHODS: This was a nationwide case-control analysis from the Taiwan National health Insurance Research Database. We analysed 16,847 female breast cancer cases among women older than 50 years who were diagnosed between January 1, 2002, and December 31, 2008. A matched control group consisted of 50,460 matched subjects. Longitudinal exposure to angiotensin-converting enzyme (ACE) inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and aspirin was compared between women who had a first-time diagnosis of breast cancer and matched controls without a diagnosis of breast cancer. RESULTS: The risk of breast cancer among patients taking both aspirin and ACEI decreased as the ACEI dose increased. Among patients receiving between 28-364 cumulative defined daily doses (cDDD) of aspirin, the adjusted ORs were 0.97 (0.90-1.06), 0.91 (0.82-1.03) and 0.79 (0.68-0.92) for women taking ACEI for 0-27, 28-364, and >365 cDDD, respectively. Among women receiving >365 cDDD of aspirin, the adjusted ORs were 0.91 (0.80-1.03), 0.81 (0.70-0.94) and 0.81 (0.71-0.92) as the ACEI dose increased, respectively. Women taking non-aspirin NSAIDs along with ACEI had the same finding. Among women taking 28 - 364 cDDD of NSAIDs, the adjusted ORs were 0.85 (0.81-0.89), 0.87 (0.81-0.94) and 0.80 (0.73-0.88) ; for women receiving >365 cDDD of NSAIDs, the adjusted ORs were 0.68 (0.62-0.74), 0.61 (0.53-0.70) and 0.60 (0.52-0.70) as the ACEI dose increased, respectively. CONCLUSIONS: The findings of this nationwide case-control analysis support the hypothesis that ACE inhibitors enhance the antitumor effect of cyclooxygenase (COX) inhibitors on breast cancer. There was no statistically significant association between use of any ACE inhibitor alone and breast cancer rates.