OBJECTIVE To study, in three separate investigations, the potential interaction between omeprazole and three different non-steroidal anti-inflammatory drugs (NSAIDs; diclofenac, naproxen and piroxicam) in healthy male and female subjects. METHODS Each investigation was an open, randomized, three-way cross-over study, in which the subjects were given omeprazole 20 mg once daily for 1 week, the NSAID in therapeutic daily doses (diclofenac 50 mg bid, naproxen 250 mg bid, or piroxicam 10 mg om), or a combination of omeprazole and each NSAID. The plasma concentrations of the NSAID as well as of omeprazole were determined on the last day of each investigation period. RESULTS None of the NSAIDs studied had any effect on the plasma concentration versus time curve (AUC) of omeprazole. It was also demonstrated that omeprazole 20 mg daily had no significant influence on the pharmacokinetics of the NSAIDs. The AUC ratio, (NSAID +omeprazole):NSAID alone, was 1.11, 0.99, and 0.99 for diclofenac, naproxen, and piroxicam, respectively. CONCLUSIONS Diclofenac, naproxen, and piroxicam can be administered together with omeprazole 20 mg daily without need for dosage alteration. There was no significant change in the bioavailability of theses NSAIDs during omeprazole therapy in this study.