Background & Aims: The use of proton pump inhibitors (PPIs) has increased rapidly in the past 2 decades. Concerns about the regular use of PPIs contributing to mortality have been raised. Methods: We conducted a prospective cohort study using data collected from the Nurses’ Health Study (2004–2018) and the Health Professionals Follow-up Study (2004–2018). Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs for mortality according to PPI use. We used a modified lag-time approach to minimize reverse causation (ie, protopathic bias). Results: Among 50,156 women and 21,731 men followed for 831,407 person-years and a median of 13.8 years, we documented 22,125 deaths, including 4592 deaths from cancer, 5404 from cardiovascular diseases, and 12,129 deaths from other causes. Compared with nonusers of PPIs, PPI users had significantly higher risks of all-cause mortality (HR, 1.19; 95% CI, 1.13–1.24) and mortality due to cancer (HR, 1.30; 95% CI, 1.17–1.44), cardiovascular diseases (HR, 1.13; 95% CI, 1.02–1.26), respiratory diseases (HR, 1.32; 95% CI, 1.12–1.56), and digestive diseases (HR, 1.50; 95% CI, 1.10–2.05). Upon applying lag times of up to 6 years, the associations were attenuated and no longer statistically significant (all-cause: HR, 1.04; 95% CI, 0.97–1.11; cancer: HR, 1.07; 95% CI, 0.89–1.28; cardiovascular diseases: HR, 0.94; 95% CI, 0.81–1.10; respiratory diseases: HR, 1.20; 95% CI, 0.95–1.50; digestive diseases: HR, 1.38; 95% CI, 0.88–2.18). Longer duration of PPI use did not confer higher risks for all-cause and cause-specific mortality. Conclusions: After accounting for protopathic bias, PPI use was not associated with higher risks of all-cause mortality and mortality due to major causes.