Background: To examine the rates and predictors of deep periprosthetic infections after primary total shoulder arthroplasty (TSA). Methods: We used prospectively collected data on all primary TSA patients from 1976-2008 at Mayo Clinic Medical Center. We estimated survival free of deep periprosthetic infections after primary TSA using Kaplan-Meier survival. Univariate and multivariable Cox regression was used to assess the association of patient-related factors (age, gender, body mass index), comorbidity (Deyo-Charlson index), American Society of Anesthesiologists class, implant fixation, and underlying diagnosis with risk of infection. Results: A total of 2,207 patients, with a mean age of 65 years (SD, 12 years), 53% of whom were women, underwent 2,588 primary TSAs. Mean follow-up was 7 years (SD, 6 years), and the mean body mass index was 30 kg/m2 (SD, 6 kg/m2). The American Society of Anesthesiologists class was 1 or 2 in 61% of cases. Thirty-two confirmed deep periprosthetic infections occurred during follow-up. In earlier years, Staphylococcus predominated; in recent years, Propionibacterium acnes was almost as common. The 5-, 10-, and 20-year prosthetic infection-free rates were 99.3% (95% confidence interval [CI], 98.9-99.6), 98.5% (95% CI, 97.8-99.1), and 97.2% (95% CI, 96.0-98.4), respectively. On multivariable analysis, a male patient had a significantly higher risk of deep periprosthetic infection (hazard ratio, 2.67 [95% CI, 1.22-5.87]; P = .01) and older age was associated with lower risk (hazard ratio, 0.97 [95% CI, 0.95-1.00] per year; P = .05). Conclusions: The periprosthetic infection rate was low at 20-year follow-up. Male gender and younger age were significant risk factors for deep periprosthetic infections after TSA. Future studies should investigate whether differences in bone morphology, medical comorbidity, or other factors are underlying these associations. © 2012.