Binding of four tricyclic antidepressants (TCAs)--imipramine, desipramine, didesmethylimipramine and amitriptyline--on the lipid part of biological membranes was studied. Heterogeneity in partitioning of these drugs in artificial lipid bilayers (liposomes) was quantified using a radioligand binding method. High-affinity binding sites on the liposomes were found and characterized by apparent dissociation constant (Kd) and by binding capacity (Bmax). Change in the membrane lipid composition affected the binding parameters of the high-affinity binding, while the ligand modification affected non-specific binding (low-affinity adsorption) of TCAs. The possible role and methodological importance of high-affinity binding to the lipid part of biological membranes are both discussed. Determination of radioligand binding on model lipid membranes is recommended to avoid certain problems in interpretation of receptor binding studies.