Of 6,133 patients, on ventilation day 3, 58.8% received H2RAs, 26.1% received PPIs, and 4.1% received sucralfate. Patients frequently changed treatment throughout follow-up. Among 4,595 patients receiving PPIs or H2RAs on day 3, we found no differences in risk estimates for ventilator mortality and extubation alive comparing daily PPI versus daily H2RA strategies: RR, mortality, 1.03 (95% CI, 0.89–1.22); extubation alive, 1.00 (95% CI, 0.96–1.03). We found similar results after accounting for PPI dose. For possible ventilator-associated pneumonia (PVAP) and infection-related ventilator-associated complication (IVAC), point estimates were larger, but the 95% CIs crossed 1.0: RR PVAP, 1.25 (95% CI, 0.80–1.94); IVAC, 0.89 (95% CI, 0.64–1.17). The magnitude of effect estimates depended on PPI dose. The RR for PVAP, high-dose PPI versus H2RA, was 1.53 (95% CI, 0.82–2.51), and for low-dose PPI versus H2RA, the RR was 0.97 (95% CI, 0.47–1.63). For IVAC, high-dose PPI versus H2RA, the RR was 1.01 (95% CI, 0.66–1.42), and for low-dose PPI versus H2RA, the RR was 0.78 (95% CI, 0.50–1.11).