Absctract Context In vitro and in vivo evidence has supported the role of angiotensin II blockade in reducing leiomyoma cell proliferation and growth. However, no population-based study to date has investigated this potential association. Objective This work aims to determine whether prior angiotensin-converting enzyme inhibitor (ACEi) use is associated with a reduced odds of leiomyoma development. Design A nested case-control study was conducted. Setting The population was assembled from the Truven Health MarketScan Research Database, which includes private health insurance claims from January 1, 2012 to December 31, 2017. Patients or Other Participants We included (n = 353 917) women age 18 to 65 with hypertension. Cases (n = 13 108) with a leiomyoma diagnosis were matched to controls (n = 340 808) with no such diagnosis at a 1:26 ratio by age and region of origin within the United States. Intervention Prior ACEi use was determined from outpatient drug claims. Main Outcome Measure Leiomyoma development was indicated by a first-time diagnosis code. Results Women on an ACEi experienced a 31.8% reduced odds of developing clinically recognized leiomyoma compared to nonusers (odds ratio [OR] 0.68; 95% CI, 0.65-0.72). This association was significant for each age group: 30 to 39 years (OR 0.86; 95% CI, 0.74-0.99), 40 to 49 years (OR 0.71; 95% CI, 0.66-0.76), 50 to 59 years (OR 0.63; 95% CI, 0.58-0.69), and 60 to 65 years (OR 0.58; 95% CI, 0.50-0.69). Of the ACEis, lisinopril (OR 0.67; 95% CI, 0.64-0.71), quinapril (OR 0.62; 95% CI, 0.41-0.92), and ramipril (OR 0.35; 95% CI, 0.23-0.50) demonstrated a significant association with reduced leiomyoma incidence. Conclusions ACEi use was associated with a reduced odds of developing clinically recognized leiomyoma in adult hypertensive women.