Previous studies have identified laboratory markers for severe Clostridium difficile infection (CDI). The most consistent of these markers is the presence of marked leukocytosis. We examined the validity of these markers as predictors of mortality in patients with CDI. We excluded patients with preexisting hematologic conditions that would be expected to impair their ability to demonstrate leukocytosis. On univariate analysis, marked leukocytosis (P = 0.02), thrombocytopenia (P = 0.008), and increased blood urea nitrogen (P < 0.001) and creatinine (P = 0.001) levels were found to be significantly associated with mortality in patients with CDI. However, on logistic regression analysis, only renal impairment was found to be an independent predictor (odds ratio, 5.07). Importantly, in our study, leukocytosis was not an independent predictor after adjustment for other variables, which may be due to our selection criteria when adjusting for confounding variables. We are therefore of the opinion that in immunocompromised hosts who are leukopenic at the time of CDI diagnosis, other laboratory markers should be identified to serve as indicators for severe disease.