The binding of four secondary and tertiary amine drugs with local anesthetic activity (propranolol, tetracaine, lidocaine, procaine) to liposomes containing charged surface groups of different chemical composition has been investigated. Binding is determined by measurement of partition coefficients and of drug induced zeta potential changes of the liposomes. For propranolol 30% of the total amount of drug dissolved in phosphatidylcholine is located as protonated form in the liposome surface. Fifty percent of tetracaine and 13% of procaine contribute to the surface charges. Negative surface charges (phosphatidylserine) facilitate drug binding and drug protonization in the liposome surface. Positive surface charges (hexadecyltrimethylammonium) prevent the protonization of the drugs. Different chemical groups of single negatively charged phospholipids or of electrostatically neutral lipids have no significant effect on drug binding which proves that binding is not influenced by steric and bulky head group configurations. The drugs interact hydrophobically with the lipid phase in such a way that the drug amine protonizes in the presence of the negatively charged phosphate oxygen of the phospholipid. Hexadecanoic acid is located deeper within the liposome surface than other negatively charged phospholipids. Correspondingly the drug action is weaker and drug protonization is prevented.