Summary Several variables have been proposed to predict the prognosis of patients with Clostridium difficile infection (CDI), but a clinically useful tool to stratify resource utilization has not been determined. Horn’s index, a severity score based on underlying clinical illness, reliably predicts patients at high risk of CDI. The purpose of this study was to assess the use of Horn’s index to stratify patients with CDI at high risk of poor clinical and economic outcomes. Hospitalized patients diagnosed with CDI were followed prospectively for three months. Horn’s index scores were calculated for each patient on the day of the positive toxin test for C. difficile, and used to stratify differences in outcome variables (length of hospital stay, mortality and hospital costs). Eighty-five CDI patients (50% male, 64% Caucasian) were recruited. Discharge mortality was 0% for patients with Horn’s index scores of 1 or 2, 5% for those with a score of 3, and 50% for those with a score of 4 ( P < 0.001). Three-month mortality was 0%, 5%, 17% and 60% for patients with Horn’s index scores of 1, 2, 3 and 4, respectively ( P = 0.0004). Median three-month hospital costs were $8585, $12,670, $29,077 and $68,708 for patients with Horn’s index scores of 1, 2, 3 and 4, respectively ( P < 0.001). Patients with Horn’s index scores of 3 or 4 had a significantly longer hospital stay [mean 33.4 (standard deviation, SD 33.3) days] than patients with scores of 1 or 2 [mean 15.1 (SD 16.2) days, P = 0.001]. This study found Horn’s index to be a simple and useful method for identifying CDI patients at high risk of poor clinical and economic outcomes.