BACKGROUND: The purpose of this study was to compare the outcome of infection (CDI) in patients on systemic steroids for various indications to patients not on steroids in term of disease severity, and associated morbidity and mortality. METHODS: We retrospectively reviewed records of all patients with CDI at our hospital from January 2011 to December 2016. Patients were evaluated for baseline characteristics, comorbidities, medications, disease severity, disease-related length of stay (LOS) from the diagnosis of CDI to discharge, need for surgical intervention, and disease-related mortality. Based on systemic steroids use, patients who were using steroids for different indications constituted the study population, and those with no steroids use were clustered as a control group. RESULTS: Of the 258 patients included, males were 127 (49%). Severe and severe-complicated CDI developed in 21/63 (33.3%) and 1/63 (1.6%) of patients on steroids (average daily dose of 20 mg), and in 73/195 (37.4%) and 5/195 (2.6%) of patients with no steroids use (P = 0.56 and P = 0.66, respectively). Surgical intervention was not required in the steroids group and 5/195 (2.7%) of patients not on steroids underwent bowel surgeries (P = 0.38). Mean LOS (days) was 11.6 ± 1.5 in the steroids group and 10.4 ± 0.7 in the no-steroids group (P = 0.4). CDI-related mortality occurred in 9/63(14.3%) of patients on steroids, and in 15/195 (7.7%) of patients not on steroids (P = 0.12; odds ratio (OR): 2; 95% confidence interval (CI): 0.8 - 4.8). CONCLUSION: There was no significant difference in the severity of CDI, need for surgical interventions, disease-related LOS and mortality in systemic steroids users compared to patients not on steroids.