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Proton pump inhibitors (PPIs) may be linked to implant failure by affecting bone metabolism and osseointegration. This study evaluated how PPIs influence long-term implant failure and peri-implantitis in PPI users and nonusers.This was a retrospective cohort study of patients treated at the Philadelphia Veterans Affairs Medical Center between 2006 and 2013. The primary predictor variable was PPI use. Outcome variables were long-term implant failure and the presence of peri-implantitis. Data gathered included demographic characteristics, medical comorbidities, implant location, and dimensions. Multivariate regression models measured independent factor associations. The final study cohort contained 933 implants placed in 284 patients. A total of 323 (32.6%) implants were placed in patients with ongoing PPI use. PPI users were less likely to smoke (22.1% vs 31.9%; P.01) and use illicit drugs (5.0% vs 9.7%; P = .01) and more likely to have undergone prior bone grafting (18.3% vs 12.9%; P = .03).PPI use lost significance after controlling for confounding factors and was not an independent predictor of implant failure (odds ratio [OR], 0.801; 95% confidence interval [CI], 0.56-1.15; P = .24) or peri-implantitis (OR, 0.801; 95% CI, 0.56-1.15; P = .24).Our study found no independent associations between PPI use and implant failure or peri-implantitis. Contrary to published literature, PPIs may not influence implant health.