The objective of the present study was to investigate the association between angiotensin-converting enzyme (ACE) inhibitor use and cancer incidence (overall, and breast, prostate, and colorectal cancers specifically) in a large representative sample of US adults. Cross-sectional data on cancer diagnosis, timing of cancer diagnosis, ACE inhibitor use, and other characteristics were extracted from 49 512 adults aged ≥ 20 years participating in the National Health and Nutrition Examination Survey (1999-2016). Multivariable-logistic and propensity score matching (PSM) regressions examined the relationship between pre-diagnosis use of ACE inhibitors and diagnosis of all cancers, and breast, prostate, and colorectal cancers specifically. Overall, we observed an increased likelihood of cancer diagnosis [odds ratio (OR) 1.269, 95% confidence interval (CI) 1.088-1.480] among those who used ACE inhibitors compared to non-ACE inhibitor use, and for prostate cancer diagnosis (OR 1.438, 95% CI 1.090-1.897), after adjusting for age, sex, body mass index, race/ethnicity, educational attainment, physical activity, alcohol drinking status, smoking status, and high blood pressure. PSM regression retrieved more conservative estimates such that the increased likelihood of cancer diagnosis was only observed when comparing ACE inhibitor users with non-drug users (OR 1.022, 95% CI 1.016-1.027). Compared with non-ACE inhibitor use, ACE inhibitor use was associated with an increased risk of prostate cancer. In conclusion, in this large representative sample of US adults, it was found that ACE inhibitor use may have a marginal influence on some cancers.