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The long-term use of angiotensin converting enzyme (ACE) inhibitors may reduce the risk of developing colorectal cancer (CRC).The aim of our study was to determine how long-term use of lisinopril influences the development of advanced adenomatous polyps (APs).We performed a retrospective study of patients who were found to have 1 or more histologically confirmed APs on an index colonoscopy, and who also had a follow-up colonoscopy 3 to 5 years later. APs found on the follow-up colonoscopy were evaluated for location, size, number, and advanced features. Patients were divided into 2 groups: (1) those who used lisinopril continuously during the interval between colonoscopies and (2) those who were lisinopril naive. Clinical factors were evaluated for their association with advanced APs in both the groups.A total of 4660 patients with a history of AP were identified. There were 1760 continuous lisinopril users and 2900 nonusers. Univariate analysis showed that patients with lisinopril use had fewer right-side APs (odds ratio=0.68, P<0.001) and fewer total number of APs (P<0.001). Lisinopril users had a 41% reduced incidence of advanced APs compared with the nonusers (odds ratio=0.59, P<0.001). A Mann-Whitney U test revealed that among lisinopril users, patients with advanced APs were on a lower dose of the medication compared with patients without advanced APs (mean dose=17.2 mg vs. 20.1 mg, respectively; P<0.001). Spearman correlation analyses indicated an inverse relationship between lisinopril dosage and number of polyps (P<0.001). There was also an inverse relationship between dosage and size of polyps (P<0.001); higher dosages of lisinopril were significantly associated with smaller size of polyps. The protective effect of lisinopril was significant even when adjusted for age, body mass index, aspirin/nonsteroidal anti-inflammatory drug use, and statin use.The use of lisinopril was associated with a 41% reduction in the incidence of advanced APs during a period of 3 to 5 years, even after adjustment for other known polyp risk factors. We speculate that long-term ACE inhibitors use may reduce the development of CRCs by reducing the development of advanced APs.