Purpose: To study the associations between long-term and short-term use of topical beta-blockers and mortality. Design: Prospective population-based cohort study. Participants: To examine long-term effects, 3842 participants aged 55 years and older were recruited. To examine short-term effects, 484 incident beta-blocker users and 4700 age-matched controls were recruited. All participants were recruited as part of the Rotterdam Study. Methods: To examine long-term effects, associations between topical beta-blocker use before and at baseline, between 1990 and 1997, and mortality between 1997 and 2005 were studied. Data were analyzed using Cox regression, and hazard ratios were adjusted for age, gender, smoking, systemic hypertension, diabetes mellitus, and angina pectoris. Short-term effects were defined as death within 3 months after the first prescription of a topical beta-blocker. Mortality was compared between incident beta-blocker users, that is, participants who started using a topical beta-blocker between the onset of the Rotterdam Study in 1990 and October 1, 2004, and age-matched controls. Short-term effects were examined using a chi-square test. Confounding by smoking was analyzed by stratification. Main Outcome Measures: For long-term effects, hazard ratios of topical beta-blocker use for all-cause mortality and cardiovascular mortality; for short-term effects, chi-square statistics between mortality of incident topical beta-blocker users and age-matched controls. Results: With regard to long-term effects, mean age at baseline was 72 years (standard deviation, 7 years). Topical beta-blockers were used by 228 participants. Seven hundred nine participants died during the follow-up (18%); 135 (3.5%) died of a cardiovascular cause. The hazard ratio of topical beta-blocker use was 0.94 (95% confidence interval [CI], 0.71-1.25; P = 0.69) for all-cause mortality and 1.02 (95% CI, 0.56-1.86; P = 0.95) for cardiovascular mortality. With regard to short-term effects, 4 (0.8%) of the 484 incident topical beta-blocker users died within 3 months after their first prescription; 65 (1.4%; P = 0.31) of the 4700 aged-matched controls died within a similar period. Conclusions: Use of topical beta-blockers seems not to be associated with excess mortality.