Hypothesis: To assess the long-term risk of revision surgery and its predictors after humeral head replacement (HHR). Methods: We used prospectively collected data from the Mayo Clinic Total Joint Registry and other institutional electronic databases. Revision-free survival for HHR at 5, 10, and 20 years was calculated by use of Kaplan-Meier survival analysis. We used univariate and multivariate-adjusted Cox regression analyses to examine the association of age, gender, body mass index (BMI), comorbidity assessed by Deyo-Charlson index, American Society of Anesthesiologists class, implant fixation (cemented vs uncemented), and underlying diagnosis with the risk of revision surgery. Hazard ratios with 95% confidence intervals (CIs) and P values are presented. Results: During the study period (1976-2008), 1,359 patients underwent 1,431 shoulder HHRs. The mean age was 63 years, 63% of patients were female, the mean BMI was 28 kg/m2, and 60% of implants were cemented. During the follow-up, 114 HHRs were revised. At 5, 10, and 20 years, the shoulder implant survival rate was 93.6% (95% CI, 92.1%-95%), 90% (95% CI, 88%-92%), and 85% (95% CI, 81.8%-88.4%), respectively. In multivariate-adjusted analyses, older age was associated with a lower hazard of revision, with a hazard ratio of 0.97 (95% CI, 0.96-0.99; P < .001), and higher BMI was associated with a higher hazard ratio of 1.04 (95% CI, 1.01-1.08; P = .02). Conclusions: Long-term survival of HHR at 20 years was excellent. Obesity and younger age are risk factors for a higher revision rate after HHR. Further studies should investigate the biologic rationale for these important associations. Surgeons can discuss these differences in revision risk with patients, especially young obese patients. © 2012.