To clarify the relationship between hemolytic activity and membrane penetration of drugs, some tranquilizers and antihistaminics were compared with each other as regards the amount of drugs able to penetrate human erythrocyte membrane at 27 and 37°C, and the activation energy for penetration was calculated. The drugs exerting strong hemolytic action penetrated the membrane much more effectively than those with less activity. The relation between the amount (A) of drug penetrated vs. extracellular drug concentration (C) could be generally described by a linear equation : log A (10-8mol)=0.817·log C (10-4M)+b. With 8 phenothiazines, the correlation coefficient between A and the value of 1/C1 or 1/C50 (C1 is the initial concentration inducing hemolysis and C50 is the concentration inducing 50% hemolysis) was 0.916 (p<0.01) or 0.927 (p<0.01), respectively. The amount of drugs penetrated at the C50 was (0.7-4.1)×10-17mol/ghost and (1.7-10.6)×10-2mol/mol phospholipid. The drug penetration into the membrane could be approximately described by the Freundlich equation, but not the Scatchard equation. The activation energy for drug penetration was in the range from 1.07 to 6.16 kcal, and there was no clear-cut relationship between the energy and the above parameters.