A multicentre, double-blind study of unprecedented size was conducted to compare the safety and efficacy of piroxicam and naproxen in the treatment of osteoarthritis. The study comprised 2,035 patients and a treatment period of 12 weeks. The dosage was 20 mg piroxicam and 750 mg naproxen daily with the option to reduce to 10 and 500 mg, respectively, at week 4 or 8. No major difference between the drugs was observed with regard to overall incidence of adverse events. The frequency of serious adverse events was about 1% for both drugs. A statistically significant decline of adverse events with age was found in both sexes. Piroxicam was significantly superior to naproxen for pain at rest and pain on movement at 12 weeks and degree of restriction in daily activity at 4 weeks. A significantly increasing beneficial effect was observed with both drugs between 4 and 12 weeks of treatment. The comparable safety observed for the two drugs is in contrast to perceptions based on spontaneous reports to official monitoring systems.