Recent studies have shown that the interaction of various tricyclic neuroleptics and antidepressants with isolated alpha 1-acid glycoprotein occurs at one common binding site and with relatively high association constants. The aim of the present study was to find differences in the binding of some phenothiazines, thioxanthenes, and several other drugs reported to bind alpha 1-AGP. The findings suggest that the affinity of the phenothiazines and thioxanthenes depends primarily on the existence of the tricyclic skeleton and is generally increased by the basic side chain. Substituents at position 3 of the phenothiazine nucleus influence the affinity in a variable way. The losses of radioactivity by non-specific absorptions to the dialysing chambers were considered for the calculation of the association constants. No correlation between association constants and the antipsychotic potency of neuroleptic drugs could be detected.