To examine the association between body mass index (BMI) and in-hospital mortality in patients presenting with Clostridium difficile infections in emergency department visits (ED) in the USA. Infected patients with extreme BMIs may have an elevated mortality risk, but prior studies examining this question have been too small to reach definitive conclusions. Data were from the Nationwide Emergency Department Sample (NEDS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality during 2012. NEDS records emergency department (ED) visits across the USA and provides statistical sampling weights to approximate a nationally representative sample of US hospital-based EDs. Inclusion criteria were adults age 18 or older with an ICD-9 code for C. difficile infection (008.45) and a documented body mass index ICD-9V code (V85.x). Logistic regression was used to predict mortality after adjusting for demographic variables and chronic comorbidities defined by Elixhauser. A weighted sample of 22,937 ED visits met all inclusion criteria. The cohort's mean age was 66. 64.6% were female. The unadjusted mortality rate was 6.5%. Patients with a BMI<19kg/m2 had an adjusted odds ratio of 2.73; 95% CI (1.80, 4.16), p<0.001 compared to patients with a BMI of 19.0-4.9kg/m2 (the referent category). In obese patients, only BMI values >40kg/m2 were associated with significantly greater mortality risk. Being underweight (BMI<19) or morbidly obese (BMI>40) was associated with increased risk of in-hospital mortality in patients presenting with C. difficile infections.