The purpose of this study was to evaluate risk factors for failure of antibiotic treatment within 30 days for uncomplicated skin infections of outpatients treated in a Veterans Affairs hospital. A retrospective chart review of outpatients between January 2006 and July 2015 with an ICD-9 (International Statistical Classification of Diseases and Related Health Problems) code of cellulitis or abscess was included in the analysis. The primary outcome was success versus failure of the antibiotic, with failure defined as another antibiotic prescribed or hospitalization within 30 days for the original indication. A total of 293 patients were included in the final analysis, 24% of whom failed within 30 days. Obesity/overweight (body mass index [BMI] of >25 kg/m) was identified in 83% of the overall population, with 16% of that population having a BMI greater than 40 kg/m An elevated mean BMI of 34.2 kg/m ( = 0.0098) was found in the subset of patients who failed oral antibiotics compared to a BMI of 31.32 kg/m in patients who were treated successfully. Additionally, the patients who failed had an increased prevalence of heart failure at 16% ( = 0.027). Using multivariate logistic regression, BMI and heart failure were determined to be significant predictors of antibiotic prescription failure. Each 10-kg/m unit increase in BMI was associated with a 1.62-fold-greater odds of failure. A diagnosis of heart failure increased the odds of failure by 2.6-fold (range, 1.1- to 5.8-fold). Outpatients with uncomplicated skin infections with an elevated BMI and heart failure were found to have increased odds of failure, defined as hospitalization or additional antibiotics within 30 days.