The safety and toxicity associated with the use of selective cyclooxygenase-2 (COX-2) inhibitors in patients with inflammatory bowel disease (IBD) has not been extensively studied. Thirty-three patients with IBD who were prescribed celecoxib or rofecoxib were identified from questionnaire during their clinic visit at the Cedars-Sinai IBD Center between 1999 and 2002. Twenty-six had Crohn's disease (CD), 6 had ulcerative colitis (UC), and 1 had indeterminate colitis (IC). Twenty-one received rofecoxib, 10 celecoxib, and 2 received both medications at different time points. Overall, 13 (39%) patients experienced disease exacerbation, 7 of which had received celecoxib and six rofecoxib. IBD exacerbation associated with COX-2 treatment did not correlate with age, disease activity, or use of immunosuppressive medications. All patients experienced flare-up of their underlying IBD within 6 weeks of initiating COX-2 therapy. Five of 13 (38%) patients had resolution of their symptoms after discontinuing the COX-2 inhibitor, but the remaining patients required additional medical therapy to control their disease. Six other patients (18%) experienced GI side effects not associated with their underlying IBD. Five developed abdominal pain, and one developed a duodenal ulcer and a circumferential ileo-colonic ulceration with GI bleeding. Treatment with COX-2 inhibitors is associated with a high incidence of exacerbation of the underlying IBD and GI-related complications.