BACKGROUND & AIMS: Intestinal microbial flora participate in the pathogenesis of inflammatory bowel disease. Because antibiotic therapy alters intestinal microbial flora, we hypothesized that use of antibiotics might decrease the risk of flare. METHODS: We conducted a case-crossover study by using the General Practice Research Database from 1989-1997. Flares of disease were identified by receipt of a new prescription for either corticosteroids or mesalamine medications after an interval of at least 4 months without prescriptions for either class of medication. The primary exposure was receipt of any antibiotics in the 60 days preceding the index date. RESULTS: Among 1205 patients with Crohn's disease, exposure to antibiotics was associated with a reduced risk of flare (adjusted odds ratio [OR], 0.78; 95% confidence interval [CI], 0.64-0.96; P = .019). The effect was strongest with more recent exposure (test for trend, P < .05). Among 2230 patients with ulcerative colitis, use of any antibiotics within 60 days was not associated with flare of disease (adjusted OR, 0.96; 95% CI, 0.82-1.12; P = .581), although a potentially protective effect was observed in those patients with very recent exposure (exposure within 15 days: OR, 0.66; 95% CI, 0.51-0.85). CONCLUSIONS: Antibiotic use within 60 days was associated with a lower risk of flare of Crohn's disease, but not ulcerative colitis. The strength of the protective effect of antibiotics in Crohn's disease wanes over time.