Background and purpose There have been no published studies assessing the possible association of medical comorbidities with periprosthetic fracture risk. We therefore assessed whether medical comorbidity is associated with risk of periprosthetic fractures after total hip replacement (THR). Material and methods We used prospectively collected data from 19892008 in the Mayo Clinic Total Joint Registry for 2 cohorts: primary THR and revision THR. The main variables of interest were Deyo-Charlson comorbidities at the time of surgery. Outcome of interest was p ostoperative periprosthetic fracture at postoperative day 1 onwards. Multivariable Cox regression models were additionally adjusted for age, sex, body mass index, American Society of Anesthesiology (ASA) class, and operative diagnosis. Results We identified 14,065 primary THRs and 6,281 revision THRs with mean follow-up times of 6.3 and 5.6 years, respectively. There were 305 postoperative periprosthetic fractures in the primary THR cohort and 330 in the revision THR cohort. In patients who underwent primary THR, 2 comorbidities were associated with higher risk of periprosthetic fracture: peptic ulcer disease with adjusted hazard ratio of 1.5 (95% CI: 1.1-2.2) and heart disease with adjusted hazard ratio of 1.7 (CI: 1.2-2.4). In patients with revision THR, peptic ulcer disease was associated with a higher adjusted risk of periprosthetic fracture, 1.6 (CI: 1.1-2.3). Interpretation Peptic ulcer disease and heart disease in primary THR patients and peptic ulcer disease in revision THR patients were associated with higher postoperative periprosthetic fracture risk. Further studies are needed to understand whether disease severity or specific medications used for treatment, or both, are responsible for this association. This may allow identification of modifiable factors. © 2011 Nordic Orthopaedic Federation.