We describe 3 AS patients treated with etanercept for active AS who developed new onset of CD while AS related symptoms responded well to etanercept. Typical symptoms of active CD occurred 11, 12, and 26 months after start of etanercept therapy, respectively. On colonoscopy, inflammatory lesions highly compatible with CD were found endoscopically and histologically in all patients. Etanercept was stopped, and CD responded well to standard treatment. One of the 3 patients was reexposed to etanercept later on. While the 2 patients without re-exposure to etanercept did not have further CD flares, the third patient flared 6 months after re-institution of etanercept in combination with azathioprine. New onset of CD may be considered as an immune-mediated injury induced by etanercept. Although this is an intriguing hypothesis, any causative role of etanercept remains unproven at this stage.