Background Deep infection after shoulder arthroplasty is a diagnostic and therapeutic challenge. The current literature on this topic is from single institutions or Medicare samples, lacking generalizability to the larger shoulder arthroplasty population. Questions/purposes We sought to identify (1) patientspecific risk factors for deep infection, and (2) the pathogen profile after primary shoulder arthroplasty in a large integrated healthcare system. Methods A retrospective cohort study was conducted. Of 4528 patients identified, 320 had died and 302 were lost to followup. The remaining 3906 patients had a mean followup of 2.7 years (1 day-7 years). The study endpoint was the diagnosis of deep infection, which was defined as revision surgery for infection supported clinically by more than one of the following criteria: purulent drainage from the deep incision, fever, localized pain or tenderness, a positive deep culture, and/or a diagnosis of deep infection made by the operating surgeon based on intraoperative findings. Risk factors evaluated included age, sex, race, BMI, diabetes status, American Society for Anesthesiologists (ASA) score, traumatic versus elective procedure, and type of surgical implant. For patients with deep infections, we reviewed the surgical notes and microbiology records for the pathogen profile. Multivariable Cox regression models were used to evaluate the association of risk factors and deep infection. Adjusted hazard ratios and 95% CI are presented. Results With every 1-year increase in age, a 5% (95% CI, 2%-8%) lower risk of infection was observed. Male patients had a risk of infection of 2.59 times (95% CI, 1.27-5.31) greater than female patients. Patients undergoing primary reverse total shoulder arthroplasty had a 6.11 times (95% CI, 2.65-14.07) greater risk of infection compared with patients having primary unconstrained total shoulder arthroplasty. Patients having traumatic arthroplasties were Each author certifies that he or she, or a member of his or her immediate family, has no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained.