IMPORTANCE Isotretinoin is the standard treatment for refractory severe nodulocystic acne.A true association between prior isotretinoin use and development of inflammatory bowel disease (IBD) is uncertain. Addressing the reality of this association is important in decision making for both the clinician and the patient when isotretinoin treatment is indicated.OBJECTIVE To assess the risk of IBD mainly in patients with acne with and without isotretinoin exposure.DESIGN, SETTING, AND PARTICIPANTS In this retrospective, single-center study, the electronic medical records of patients who were primarily seeking acne treatment were reviewed for isotretinoin exposure. International Classification of Diseases, Ninth Revision (ICD-9) codes were used to search for IBD diagnosis. participants included 1078 patients from 1995 to 2011,with isotretinoin referenced in their medical records, and who had ongoing local medical care defined as having had a serum sample collected between 2006 to 2011 for any reason while an Olmsted County, Minnesota, resident at the time of serum sample collection.EXPOSURES The exposed group included the patients with confirmed prior isotretinoin exposure (n = 576), and the nonexposed group were defined as patients who never received isotretinoin or received it after the diagnosis of IBD (n = 502).MAIN OUTCOMES AND MEASURES Risk of IBD among isotretinoin-exposed vs non exposed patients.RESULTS Both groups were comparable by race, prior systemic antibiotic use, and systemic tetracycline use. Inflammatory bowel disease developed less frequently in the isotretinoin-exposed group vs the nonexposed group (0.9%vs 2.6%; P = .03; unadjusted odds ratio [OR], 0.33; 95%CI, 0.12-0.93; P = .04). The negative association between isotretinoin exposure and IBD remained after adjusting for sex (OR, 0.28; 95%CI, 0.10-0.80;P = .02) and for sex and non acne indication (OR, 0.28; 95%CI, 0.10-0.79; P = .02).CONCLUSIONS AND RELEVANCE Our study did not show an increased risk of IBD with prior isotretinoin use. If anything, the risk seemed to be decreased. Although these results may be due to chance given the small number of IBD cases, the anti-inflammatory and immune-modulating effects of isotretinoin may be worth exploring.