Background: Treatment of Clostridium difficile infection (CDI) is often limited by recurrence in 25% of cases. The objective of this study was to determine risk factors of CDI recurrence during a provincial endemic. Methods: Data was prospectively collected for 1 year in a Montr�al hospital. Inclusion criteria were: age ?18 years; admission for ?72 h; CDI diagnosis during current admission; no CDI diagnosis in the previous 3 months. Results: A total of 121 patients were included, of which 42% were female. Mean age was 77 years old, with a median Charlson comorbidity index of 5. Forty patients (33%) had recurrent disease within 2 months of initial CDI treatment. There were 20 deaths (17%) within the 2-month follow-up period. Higher risk of CDI recurrence was independently associated with older age (HR = 2.26 for each decade), female gender (HR = 1.56), and lymphopenia at completion of CDI treatment (HR = 2.18), while a positive C. difficile antitoxin serology was protective (HR = 0.17). CDI recurrence was not associated with lymphopenia at time of diagnosis, underlying comorbidities, severity or treatment of the initial CDI episode, or re-exposure to antibiotics during the follow-up period. Conclusion: Lymphopenia at the end of CDI treatment appears to be a strong marker for CDI recurrence. This available and inexpensive test may identify patients who are at higher risk of CDI recurrence.