Objective. To assess the association of specific comorbidities with periprosthetic fractures after primary total knee replacement (TKR). Methods. We used the prospectively collected data in the Mayo Clinic total joint registry from 1989-2008 on all patients who had undergone primary TKR. The outcome of interest was postoperative periprosthetic fractures during followup. The main predictors of interest were comorbidities grouped from the validated Deyo-Charlson index. Multivariableadjusted Cox regression analyses were adjusted for sex, age, body mass index (BMI), American Society of Anesthesiology (ASA) class, operative diagnosis, and implant fixation. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated. Results. We included 17,633 primary TKRs with a mean followup of 6.3 years. The mean age was 68 years, 55% were women, and the mean BMI was 31 kg/m 2. There were 188 postoperative periprosthetic fractures on postoperative day 1 or later; 162 fractures (86%) occurred on postoperative day 90 or later. In multivariable analyses that simultaneously adjusted for all comorbidities and other variables (age, sex, BMI, ASA, operative diagnosis, and cement status), the following 2 conditions were significantly associated with an increased hazard of postoperative periprosthetic fractures: peptic ulcer disease (HR 1.87, 95% CI 1.28-2.75; P = 0.0014) and chronic obstructive pulmonary disease (HR 1.62, 95% CI 1.10-2.40; P = 0.02). Conclusion. Peptic ulcer disease and chronic obstructive pulmonary disease are associated with a higher risk of periprosthetic fractures after primary TKR. This may be related to the disease or its treatments, which need further study. Identification of specific risk factors may allow for implementation of intervention strategies to reduce this risk. © 2011 American College of Rheumatology.