The efficacy and tolerability of etodolac and piroxicam were compared in patients with osteoarthritis of the knee. Two hundred and twenty patients entered a double-blind, parallel group trial and were randomly assigned to receive 300 mg etodolac twice daily (n = 112) or 20 mg piroxicam once daily (n = 108) for 8 weeks. The etodolac group showed significant improvement (p less than 0.05) from baseline in all efficacy assessments at all evaluations. The piroxicam group showed improvement from baseline in all efficacy assessments at all evaluations except for erythema at Week 2. While mean change from baseline was similar for both groups, the patients' and physicians' final overall evaluations showed that the etodolac-treated patients improved slightly more from baseline than the piroxicam-treated patients. Twenty (18%) patients in the etodolac group reported at least one drug-related study event. In the piroxicam group, 16 (15%) patients reported at least one drug-related study event. Twelve (11%) etodolac-treated patients prematurely withdrew from the study. Of these, 7 had at least one adverse reaction. Two of the 12 patients withdrew because of lack of efficacy. Withdrawals from the piroxicam group were comparable. Thirteen (12%) patients withdrew, 6 of whom had at least one adverse reaction. One of these patients suffered a cardiovascular accident and died. Three patients withdrew because of lack of efficacy. The results of this study indicate that etodolac and piroxicam are comparable in efficacy and tolerability for the treatment of patients with osteoarthritis.