THE LAUNCH OF THE CYCLOOXYGENASE-2 (COX-2) selective NSAIDs was based on 2 hypotheses: (1) the major adverse effects limiting the usefulness of nonselective NSAIDs are gastrointestinal in nature and (2) COX-2 selective NSAIDs are associated with fewer gastrointestinal adverse effects than nonselective NSAIDs. At the time of the launch, neither of these hypotheses had been proven and, as documented in this review, both remain uncertain. The increased incidence of total and nongastrointestinal serious adverse events, with the COX-2 selective NSAIDs as compared with nonselective NSAIDs, in the Celecoxib Long-term Arthritis Safety Study (CLASS) and the Vioxx Gastrointestinal Outcomes Research (VIGOR) study remains a major concern. The increased morbidity associated with the COX-2 selective NSAIDs may be a manifestation of the COX-2 selectivity of rofecoxib and celecoxib or the supramaximal doses of these drugs used in the trials. Proof that the increased harm was not caused by the COX-2 selectivity of the drugs depends on demonstration in a randomized controlled trial that COX-2 selective NSAIDs at usual doses are as effective as nonselective NSAIDs and cause fewer gastrointestinal serious adverse events without increasing the incidence of total nongastrointestinal serious adverse events.