The efficacy and safety of two once-daily nonsteroidal anti-inflammatory drugs (NSAIDs) were compared in a single-center, double-blind, randomized, parallel-group study. Sixty patients with rheumatoid arthritis received either extended-release ketoprofen 200 mg or piroxicam 20 mg once daily for 3 weeks. Both treatments produced significant improvements from baseline in the primary efficacy variables (physician's global assessment, patient's global assessment, number of tender joints, number of swollen joints) at most visits. There were no statistically significant differences between treatments in any efficacy variable except the number of tender joints at week 3, favoring piroxicam. Both treatments improved the quality of sleep. Pharmacokinetic/pharmacodynamic evaluations were conducted on a subset of 29 patients, aged 57 to 71 years. No statistically significant differences in the pharmacokinetic parameters were noted between the first and last dose of extended-release ketoprofen; that is, there was no accumulation of ketoprofen. In contrast, a fourfold increase in peak concentration, a twofold increase in area under the concentration-time curve (AUC), and a 53% reduction in clearance were observed in piroxicam-treated patients. There was a direct relationship between AUC at steady state and three of four efficacy variables for ketoprofen. No correlation between the efficacy scores and trough plasma levels was seen with either drug. There were no significant differences between treatments in the number of adverse events. Elevated mean blood urea nitrogen levels and relative hyponatremia persisted 1 week after the end of treatment in piroxicam-treated patients. The results of this study indicate that extended-release ketoprofen and piroxicam are therapeutically comparable. However, extended-release ketoprofen, in contrast to piroxicam, reached steady state after the first dose, was rapidly cleared, and did not accumulate over the 3-week study period.