Plasma samples from 237 patients with osteoarthritis treated with 750 mg naproxen daily were obtained after four weeks of active therapy. The samples were subjected to equilibrium dialysis, analyzed by high-performance liquid chromatography, and free concentrations and unbound fractions were determined. Within the free plasma concentration range in this large patient group, we could detect no association between free naproxen concentration and efficacy score or between free concentrations and adverse events. Free concentrations were 0.295 +/- 0.260 microgram/ml (mean +/- SD) and unbound fractions were 0.33 +/- 0.24%. Females had 65% higher free concentration compared to males (p less than 0.001). For females, but not for males, there was a statistically significant correlation (p less than 0.005) between age and free concentration. The free concentration was estimated to be 88% higher in an 80-year-old female compared to a 50-year-old. Females had a 41% higher unbound fraction than males (p less than 0.005). For females, but not for males, a statistically significant relationship between age and unbound fraction was found. The unbound fraction was estimated to be 62% higher in an 80-year-old female than in a 50-year-old.