Background Recent studies have raised concerns about the reduced efficacy of citalopram when used concurrently with proton pump inhibitors. The aim of this study was to evaluate the associations between clinical use of citalopram and omeprazole and the risk of sudden cardiac arrest (SCA) in an Asian population. Methods and Results A retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohorts comprised 3882 patients with citalopram use alone, 31 090 patients with omeprazole use alone, and 405 patients with concomitant use of citalopram and omeprazole (as the exposed cohort), and 141 508 patients received treatment with antidepressants without the risk of SCA and/or proton pump inhibitors other than omeprazole (as the comparison cohort). The primary outcome was the occurrence of SCA. The hazard ratios and 95% CIs derived from the time-dependent Cox regression model were used to assess the association between the proposed drug treatments and risk of SCA. The adjusted hazard ratios of SCA was 1.32 (95% CI, 1.17-1.50) for citalopram use alone, 1.08 (95% CI, 0.98-1.20) for omeprazole use alone, and 2.23 (95% CI, 1.79-2.78) for concomitant use of citalopram and omeprazole. The cumulative incidence of SCA over the Kaplan-Meier curves was more pronounced in patients with concomitant use of citalopram and omeprazole than those treated with citalopram alone and omeprazole alone. Conclusions This cohort study demonstrated use of citalopram and omeprazole either in isolation use or in concomitant use to be at increased risk for SCA.