A modification of the erythrocyte partitioning method for the rapid estimation of plasma-free drug fractions (fu) is described and applied to five basic drugs. In the procedure, which uses readily available clinical laboratory equipment, fu is calculated from measurements of drug partitioning between plasma and erythrocytes, and between buffer and erythrocytes. Results obtained are compared with those from equilibrium dialysis or ultrafiltration techniques for amitriptyline, imipramine, quinidine, lidocaine, and propranolol. For each drug, the mean value of fu obtained with the erythrocyte partitioning procedure was not found to be significantly different from that determined by one of the two other classical techniques. The erythrocyte partitioning method lead to reproducible (mean C.V. = 6.25) and precise values of fu when compared to the other methods; its clinical application to lidocaine gave results which agreed with those obtained by equilibrium dialysis.