The protein binding of two basic drugs, alprenolol and imipramine, and the acidic drug, naproxen, was determined in plasma obtained from 23 healthy subjects. A 2-fold variation was found between individuals in the free fraction of the two bases, while the range was even greater with naproxen. The free fraction correlated with the plasma concentration of alpha 1-acid glycoprotein for alprenolol (r = -0.75, p less than 0.001) and imipramine (r = -0.78, p less than 0.001), while there was no correlation for naproxen (r - 0.24, p greater than 0.1). This confirms recent experiments which showed that isolated alpha 1-acid glycoprotein avidly bound both alprenolol and imipramine. Drug binding, however, did not correlate with albumin concentration, although experiments with isolated albumin demonstrated its unusually high affinity for naproxen.