The aim of this retrospective large-scale study was to investigate long-term the association between proton pump inhibitors (PPIs) and risk of dental implant failure. This is a retrospective analysis of a cohort of patients rehabilitated with dental implants in the dental clinics of the universities that contribute data to the BigMouth network. Patients' characteristics including age, gender, ethnicity, race, tobacco use, systemic medical conditions, and intake of PPIs were analysed. Implant failure was defined as the removal of a dental implant for any reason. A total of 20,274 patients who received a total of 50,333 dental implants over a 12-year period were included. At the patient level, omeprazole users exhibited 1.77 (95% CI: 1.30 to 2.42) odds of experiencing implant loss compared with non-users. The use of PPIs was significantly associated with implant loss, with PPI users demonstrating 1.40 (95% CI: 1.04 to 1.88) odds of implant failure. At the implant level, implants placed in pantoprazole users showed a significant protection against implant loss, while implants in omeprazole users demonstrated a significantly lower survival time compared with those in non-users. Cox regression analysis demonstrated that implants placed in omeprazole users exhibited a significantly higher hazard ratio (HR: 1.45, 95% CI: 1.07 to 1.96) compared with those placed in non-users. Within the limitations of this study, omeprazole was significantly associated with implant failure both at a patient and implant level. At patient level, PPI users demonstrated a significantly higher risk of dental implant failure.