Rofecoxib is a selective cyclooxygenase-2 inhibitor that has been approved for the treatment of osteoarthritis and management of acute pain. Recent debate has emerged regarding the prothrombotic potential and the cardiovascular safety of this new drug, especially at doses greater than 25mg. We describe two extensively investigated cases of self-limited ischemic colitis in patients who were briefly treated with 50mg rofecoxib daily for acute pain. In both cases, the onset of symptoms correlated temporally with rofecoxib use and symptoms abated with drug discontinuation. There was no evidence of other possible causes of colon ischemia. A causal relationship between the start of rofecoxib treatment and the colon ischemia cannot be definitely established on the basis of the evidence, but the temporal relationship is striking and the pathophysiological rationale could be founded.