Purpose: Osteoarthritis (OA) of the knee has been reported to be associated with a distinct pathogenesis and clinical profile when compared to OA of the hip. Furthermore, some authors have postulated that knee OA in particular is marked by low-grade systemic inflammation. However, it is unclear whether this is additionally associated with differences in the prevalence of other medical comorbidities that have been reported to be associated with a low-grade systemic inflammatory state. Thus, the purpose of the present study was to assess whether individuals with end-stage knee OA are more likely to have medical comorbidities marked by systemic inflammation as compared to those with end-stage hip OA. Methods: All patients who underwent primary total knee (TKA) or hip arthroplasty (THA) for a diagnosis of OA were extracted from the 2010 to 2012 American College of Surgeons National Surgical Quality Improvement Project databases. Combined, these databases include preoperative risk factor and 30 day postoperative morbidity data from 374 clinical sites in North America, abstracted by trained reviewers. The study cohort encompassed 54,022 cases, including 33,906 of knee OA and 20,116 of hip OA. Patient data extracted included age, gender, and body mass index (BMI) stratified by World Health Organization (WHO) class. Comorbidities evaluated included hypertension requiring medication, diabetes, and metabolic syndrome (defined as BMI of 30 kg/m2 or greater as well as the presence of hypertension and diabetes). Additionally, smoking status within one year of surgery and chronic systemic steroid use within 30 days of surgery were abstracted. Descriptive statistics were obtained. Bivariate analyses were performed using the chi-square statistic for categorical variables, and the Student’s t-test for continuous variables. Logistic regression analysis was performed to determine whether the odds of the presence of the comorbidities of interest differed between the knee and hip groups, adjusted for covariates. Results: Knee OA patients were significantly older (mean age 67.1 vs 65.7 years; p < 0.001), had a higher prevalence of obesity (61.4% vs 44.6%; p < 0.001), and encompassed a greater proportion of women (62.7% vs 56.4%; p < 0.001) compared to hip OA patients. A significantly greater proportion of knee OA patients were being treated for hypertension (66.8% vs 58.2%; p < 0.001), had diabetes (17.7% vs 8.8%; p < 0.001), and met criteria for metabolic syndrome (3.5% vs 1.7%; p < 0.001). Controlling for age, gender, class of obesity, smoking, and chronic systemic steroid use, knee OA patients had significantly greater odds of a diagnosis of hypertension (OR 1.11; 95% CI [1.06–1.16]) and diabetes (OR 1.35; 95% CI [1.27–1.42]), and of meeting the criteria for metabolic syndrome (OR 1.35; 95% CI [1.18–1.54]). Conclusions: While arthroplasty patients with knee OA are marked by differences in demographic profile compared to those with hip OA, the results of the present study demonstrate that these variations alone fail to explain observed discrepancies in the prevalence of associated patient comorbidities. Even when controlled for demographic profile, smoking, and chronic steroid use, patients with knee OA continued to have significantly greater odds of an associated diagnosis of hypertension, diabetes, or the presence of metabolic syndrome. These findings further support the notion that knee OA is marked by unique associations with systemic disease. Further work is needed to better understand the nature of these associations, as well as to investigate potential interactions between these conditions, each of which has been reported to be independently associated with a systemic inflammatory state.