The neuroleptic radioreceptor assay (NRRA) is used widely to monitor total neuroleptic-like activity (NLA) in patients taking one or more antipsychotic drugs. The original report of Creese and Snyder (1) stated that serum alone caused a small effect on binding which was negligible compared to normal daily variations in the assay. Conversely, in studies with striata from rat or cow brain, we found that sera from healthy, drug free volunteers, when used at 50 microL/1 mL assay volume, caused marked inhibition of binding. Although any sample of serum causes reproducible inhibition with a given preparation of bovine or rat striatal membranes, the effects of various serum samples may differ markedly when several striatal membrane preparations are compared. Moreover, samples taken from people at different times may also vary, although less than the interindividual differences. Despite this variance, the slopes of log-logit plots were equal to 1 either in the presence or absence of serum. Because of the differences in the interaction of individual sera with different membrane preparations, it is difficult to compensate accurately for this serum effect by simply including control serum in the standard curve. Thus, the use of the NRRA as a quantitative tool in the clinical pharmacology of neuroleptics may be limited by this non-specific effect of serum, and this finding may offer one explanation for some of the inconsistencies found in comparing the NRRA with direct analytical methods.