Purpose: To investigate the association between the intake of proton pump inhibitors (PPIs) and the risk of dental implant failure. Materials and Methods: The present retrospective cohort study is based on patients consecutively treated between 1980 and 2014 with implant-supported/retained prostheses at one specialist clinic. Modern endosseous dental implants with cylindrical or conical design were included, and only complete cases were considered; ie, only those implants with information available for all variables measured were included in the regression model analysis. Zygomatic implants and implants detected in radiographies but without basic information about them in the patients' files were excluded from the study. Implant- and patient-related data were collected. Multilevel mixed-effects parametric survival analysis was used to test the association between PPI exposure (predictor variable) and risk of implant failure (outcome variable), adjusting for several potential confounders. Results: A total of 3,559 implants were placed in 999 patients, with 178 implants reported as failures. The implant failure rates were 12.0% (30/250) for PPI users and 4.5% (148/3,309) for nonusers. A total of 45 out of 178 (25.3%) failed implants were lost up to abutment connection (6 in PPI users, 39 in nonusers), with an early-to-late failure ratio of 0.34:1. The intake of PPIs was shown to have a statistically significant negative effect for implant survival rate (HR 2.811; 95% CI: 1.139 to 6.937; P = .025). Bruxism, smoking, implant length, prophylactic antibiotic regimen, and implant location were also identified as factors with a statistically significant effect on the implant survival rate. Conclusion: This study suggests that the intake of PPIs may be associated with an increased risk of dental implant failure. Keywords: dental implant, failure, multilevel mixed effects parametric survival analysis, multivariate analysis, proton pump inhibitors, risk factors