Background and Objectives: Maintenance of a firm and long-term stable osseointegration is the primary goal of implant dentistry. Time is used to define implant failure characteristics. Early implant failure (EIF) occurs up to one year after loading. Recent studies indicated an association between proton pump inhibitors (PPI) therapy and failure of osseointegration. The present study assessed whether the use of PPIs is a risk factor to EIF. Materials and methods: A retrospective cohort study including 687 patients and 2971 dental implants. The study group (PPIs users) comprised 17.3% (119) individuals and 18.7% (555) implants. The remaining cohort (82.7% (568) individuals and 81.3% (2416) implants) served as control. The information was taken from the patients’ files. The following information was collected: age, gender, physical status, systemic diseases, HbA1C values before and after implant-supported prosthesis delivery in cases of diabetes mellitus, smoking, implant location, number of implants per individual, bone augmentation, implant brand, length and width, and EIF. EIF was defined as implant removal within a period of up to 12 months from loading. Results: EIF in PPIs vs. non-PPIs users was 19.3% vs. 14.3% (p = 0.16) at patient level and 5.4% vs. 3.5% at implant level (p = 0.03). Univariate analysis yielded factors significantly associated with PPIs use, including older age, physical status of the American Society of Anesthesiology (ASA) 3, hypertension, hyperlipidemia, diabetes mellitus, osteoporosis, cardiovascular accident (CVA), location (anterior mandible), shorter and narrower implants, and higher number of implants per individual. Multivariate analysis yielded statistically significant OR of 1.91; p = 0.01 for EIF following PPIs use and 2.3; p < 0.001 for location in anterior mandible. Conclusions: Patients and their healthcare providers are advised to carefully consider the potential risks of taking PPIs prior to dental implant surgery. Further research is needed to confirm these risks and elucidate systemic and local factors that may be involved in such outcomes.