β-Blockers have been reported to exhibit potential anticancer effects in cancer cell lines and animal models. However, clinical studies have yielded inconsistent results regarding cancer outcomes and cancer risk when β-blockers were used. This study investigated the association between propranolol and cancer risk.Between January 1, 2000 and December 31, 2011, a patient cohort was extracted from the Longitudinal Health Insurance Database 2000, a subset of the Taiwan National Health Insurance Research Database. A propranolol cohort (propranolol usage >6 months) and nonpropranolol cohort were matched using a propensity score. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of cancer associated with propranolol treatment.The study sample comprised 24,238 patients. After a 12-year follow-up period, the cumulative incidence for developing cancer was low in the propranolol cohort (HR: 0.75; 95% CI: 0.67-0.85; P < 0.001). Patients with propranolol treatment exhibited significantly lower risks of cancers in head and neck (HR: 0.58; 95% CI: 0.35-0.95), esophagus (HR: 0.35; 95% CI: 0.13-0.96), stomach (HR: 0.54; 95% CI: 0.30-0.98), colon (HR: 0.68; 95% CI: 0.49-0.93), and prostate cancers (HR: 0.52; 95% CI: 0.33-0.83). The protective effect of propranolol for head and neck, stomach, colon, and prostate cancers was most substantial when exposure duration exceeded 1000 days.This study supports the proposition that propranolol can reduce the risk of head and neck, esophagus, stomach, colon, and prostate cancers. Further prospective study is necessary to confirm these findings.