Thirteen patients with osteoid osteoma were enrolled in a prospective trial to test whether rofecoxib, a selective cyclooxygenase-2 inhibitor, is as effective for pain control as acetylsalicylic acid. Each patient documented the pain level using a visual analog scale, with 0 being no pain and 10 being unbearable pain, during 2 days of no pain medication, 4 days of 500 mg acetylsalicylic acid three times a day, and 10 days of 25 mg rofecoxib once a day. Oral administration of 500 mg acetylsalicylic acid three times a day led to a significant decrease in pain at night, pain at rest, and pain induced by exercise. Twenty-five milligrams rofecoxib given once a day at midday showed the same remarkable improvement in pain at night, pain at rest, and pain induced by exercise. Rofecoxib in comparison with acetylsalicylic acid showed a trend toward lower pain levels in all categories. Rofecoxib offered a significantly better reduction in pain at rest during the day than did acetylsalicylic acid. Results of the current study suggest that pain induction in osteoid osteoma is related to cyclooxygenase-2, an enzyme that is blocked by acetylsalicylic acid and rofecoxib. Conservative medical treatment with rofecoxib for osteoid osteoma is recommended when percutaneous intervention is associated with significant morbidity.