Background: The objective of this study was to assess the frequency of, and risk factors for, periprosthetic fractures during and after shoulder arthroplasty. Methods: All adults treated with a primary total shoulder arthroplasty or humeral head replacement at the Mayo Clinic Medical Center from 1976 to 2008 were identified. Periprosthetic fractures were validated by medical record review. Univariate and multivariable-adjusted logistic regression analyses were used to assess the association of demographic factors (age, sex, and body mass index [BMI]), underlying diagnosis, implant fixation (cemented or uncemented), American Society of Anesthesiologists (ASA) class, and comorbidity as assessed with the Deyo-Charlson index. Results: The cohort consisted of 2207 patients treated with a total of 2588 primary total shoulder arthroplasties and 1349 patients treated with 1431 humeral head replacements. Seventy-two medical-record-confirmed periprosthetic fractures occurred in association with the total shoulder arthroplasties. These consisted of forty-seven intraoperative fractures (forty humeral fractures, five glenoid fractures, and two fractures for which the site was unclear) and twenty-five postoperative fractures (twenty humeral fractures, three glenoid fractures, and two fractures for which the site was unclear). There were thirty-three fractures associated with the humeral head replacements. Fifteen were intraoperative (eight humeral fractures and seven glenoid fractures), and eighteen were postoperative (sixteen humeral fractures and two glenoid fractures). In the multivariable regression analysis of the total shoulder arthroplasties, female sex (odds ratio [OR], 4.19; 95% confidence interval [CI], 1.82 to 9.62; p < 0.001; a 2.4% rate for women versus 0.6% for men) and the underlying diagnosis (p = 0.04; posttraumatic arthritis: OR, 2.55; 95% CI, 0.92 to 7.12) were associated with a significantly higher risk of intraoperative humeral fracture in general, and female sex was associated with the risk of intraoperative humeral shaft fracture (OR, infinity; p < 0.001). In combined analyses of all patients (treated with either total shoulder arthroplasty or humeral head replacement), a higher Deyo-Charlson index was significantly associated with an increased risk of postoperative periprosthetic humeral shaft fracture (OR, 1.27; 95% CI, 1.11 to 1.45); p < 0.001), after adjusting for the type of surgery (total shoulder arthroplasty or humeral head replacement). Conclusions: The overall risk of periprosthetic fractures after total shoulder arthroplasty or humeral head replacement was low. Women had a significantly higher risk of intraoperative humeral shaft fracture. The underlying diagnosis (especially posttraumatic arthritis) was significantly associated with the risk of intraoperative humeral fracture, and comorbidity was significantly associated with the risk of postoperative humeral shaft fracture. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. Copyright © 2012 by The Journal of Bone and Joint Surgery, Incorporated.