Clostridium difficile infection (CDI) is mediated by actions of toxin A and toxin B. Fully human monoclonal antibodies directed against the binding domains of these toxins were developed. Despite preclinical studies suggesting efficacy for the anti-toxin A monoclonal, actoxumab, the anti-toxin B monoclonal, bezlotoxumab, alone was shown to be effective in clinical trials. Intravenous infusion of bezlotoxumab at a 10 mg/kg dosage as adjunctive treatment reduced the risk of recurrent CDI over placebo for adult patients at increased risk for CDI recurrence in 2 large randomized, double-blind trials. Significant benefit was noted for patients with 1 or more of the following predefined risks: age >65 years, history of CDI, immunocompromise, severe CDI. Overall, bezlotoxumab appeared to be safe; however, an unexplained increased risk of heart failure was noted for patients with underlying congestive heart failure. Further refinement of who would benefit most and when best to administer bezlotoxumab is warranted.