OBJECTIVES: This study aimed to compare the effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk and outcomes of sepsis in patients with chronic obstructive pulmonary disease. DESIGN: A retrospective study. SETTING: Taiwan's National Health Insurance Research Database. PATIENTS: All patients with chronic obstructive pulmonary disease who received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for more than 90 days between 2000 and 2005 were recruited for this study. Pairwise matching (1:1) of the angiotensin-converting enzyme inhibitor and angiotensin receptor blocker groups resulted in two similar subgroups with 5,959 patients in each. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was sepsis, and the secondary outcome was death. The occurrence rate of sepsis was 3.67 per 100 person-years for the patients receiving angiotensin-converting enzyme inhibitors and 2.87 per 100 person-years for those receiving angiotensin receptor blockers. In addition, the patients receiving angiotensin-converting enzyme inhibitors had a higher risk of septic shock (adjusted hazard ratio, 1.45; 95% CI, 1.26-1.67) and mortality (adjusted hazard ratio, 1.31; 95% CI, 1.22-1.40) than those receiving angiotensin receptor blockers. No matter whether the patients had prior severe exacerbation before the index date, those receiving angiotensin-converting enzyme inhibitors had a higher risk of sepsis, septic shock, and mortality than those receiving angiotensin receptor blockers (all p < 0.001). CONCLUSIONS: Angiotensin receptor blockers were associated with lower rates of sepsis and mortality than angiotensin-converting enzyme inhibitors in the patients with chronic obstructive pulmonary disease. The similar findings were also noted in subgroup analysis.