Purpose The prospective assessment of Clostridium difficile infection (CDI) impact in inflammatory bowel disease (IBD) flare in outpatient setting has been poorly investigated. We aimed to evaluate the prevalence and the associated factors with CDI in IBD outpatients presenting colitis flares as well as the outcomes following treatment. Methods In this prospective cohort study, conducted from October, 2014, to July, 2016, 120 IBD patients (55% presenting colitis flare) and 40 non-IBD controls were assessed for CDI. Multivariate regression analysis was performed to identify predictors of CDI. Outcome analysis was estimated for recurrent CDI, hospitalization, colectomy, and CDI-associated mortality. Results The number of patients with CDI was significantly higher in IBD patients experiencing flares than in both inactive IBD and non-IBD groups (28.8 vs. 5.6 vs. 0%, respectively; p  = 0.001). Females (OR = 1.39, 95% CI, 1.13–17.18), younger age (OR = 0.77, 95% CI, 0.65–0.92 ) , steroid treatment (OR = 7.42, 95% CI, 5.17–40.20), and infliximab therapy (OR = 2.97, 95% CI, 1.99–24.63) were found to be independently associated with CDI. There was a dose-related increase in the risks of CDI on patients which had taken prednisone. Those treated with vancomycin had a satisfactory response to therapy, but 21% presented recurrent CDI and 16% were hospitalized. Neither necessity of colectomy nor mortality was noticed in any patient during the investigation. Conclusions In IBD outpatients presenting colitis flares, CDI is highly prevalent. Females, younger age, infliximab, and notably steroid therapy were independently associated with CDI. Most patients with CDI experienced mild-to-moderate disease, and prompt treatment with vancomycin was highly effective, which seems to reduce the serious complication risks.