Forty‐seven patients with rheumatoid arthritis (mean duration 5.7 years) who were receiving neither disease‐modifying drugs nor corticosteroids were enrolled in a 12‐week, multicenter study of the relationship between clinical and serologic measures of disease activity in patients taking nonsteroidal antiinflammatory drugs. After a 2‐week drug washout period, patients received flurbiprofen (200 mg/day) or sustained‐release ibuprofen (2,400 mg/day) for a 10‐week trial. Clinical response was assessed biweekly using standard clinical parameters, including 50‐foot walk time, tender joint score, duration of morning stiffness, and global assessment of disease activity and pain (by both the patient and the physician). Patients were classified as responders if there was ⩾30% improvement in at least 3 of the 4 clinical measures of disease activity. Thirty patients completed at least 8 weeks of therapy; there were 12 responders and 18 nonresponders. Of the laboratory parameters examined, the responders, but not the nonresponders, demonstrated significant reductions (from postwashout values) in levels of IgM rheumatoid factor and C‐reactive protein (CRP), along with significant increases in the number of circulating lymphocytes and decreases in the number of circulating granulocytes (P ⩽ 0.05). In contrast, the nonresponders demonstrated either no change or worsening of the laboratory correlates of disease activity. The responders also appeared to have more aggressive disease at baseline, with significantly more painful joints, greater 50‐foot walk times, elevated CRP values, and elevated erythrocyte sedimentation rates (P ⩽ 0.05). These data suggest that there is a subset of rheumatoid arthritis patients in whom clinical improvement with nonsteroidal antiinflammatory drug therapy is associated with significant reductions in IgM rheumatoid factor and CRP levels.