In an attempt to determine the antigenic combining sites of drug-dependent antibodies in patients with drug-related immune haemolysis, we have assessed the reactivity of 35 nomifensine-induced antibodies against human red blood cells (RBC) in the presence of 11 closely related compounds: nomifensine, its three main metabolites including their methoxylated analogues and diclofensine with its three main metabolites. Three types of antibody reactivity patterns could be differentiated: Firstly, antibodies most strongly reactive with nomifensine (n = 12); secondly, antibodies primarily directed against one of its main metabolites (n = 7), and thirdly, antibodies optimally reactive with its unknown metabolites (n = 16). The antibodies preferentially directed against nomifensine showed varying cross reactions with nomifensine-related compounds and in almost all cases also with diclofensine and/or its metabolites. Those antibodies which were optimally reactive with metabolites reacted only with nomifensine-derived compounds and only one of them was non-crossreactive. The third group of antibodies showed no (n = 12) or only weak (n = 4) cross reactions with nomifensine and/or its metabolites. Although none of the substances used bound firmly to RBC, certain blood groups have been identified in previous studies to be defined. RBC antigens were required for the reaction in approximately 40% of all antibodies, independent of their reactivity with the compounds. Thus, even when the specificity of some antibodies appeared to be predominantly controlled by certain structural features of the compounds, the actual antigenic combining site of each antibody was different and seemed to comprise parts of the drug-related determinants as well as different constituents on RBC membranes. These findings indicate firstly that RBCs function as 'carrier-like' macromolecules, since they are directly involved in the reaction; secondly, that the drugs and their metabolites act as 'pseudohaptens', in as much as they do not bind tightly to the cells; and, thirdly, that the determinants which govern the immune response appear to result from an accidental attachment rather than from a predetermined selection of antigenic membrane structures, since each antibody shows a unique reaction pattern.