Membrane fluidity and adrenergic receptor binding were studied in platelets of depressed patients before and during treatment with desmethylimipramine to investigate the relationship between the alpha 2-adrenergic receptor and its membrane environment in depression. Most samples came from a previous study in which we observed higher 3H-para-aminoclonidine (3H-PAC) binding in platelets from depressed patients compared to healthy subjects. Fluidity was measured by steady state diphenylhexatriene (DPH) anisotropy in both purified plasma membranes and in intracellular membrane preparations from platelets. No differences were observed in DPH membrane fluidity, per se, indicating that fluidity changes probably do not underlie either the increased alpha 2-adrenergic receptor binding in depression or the normalization of binding during treatment. However, lower intracellular membrane fluidity was correlated with higher binding to 3H-PAC site-1 in healthy subjects, but not in depressed patients. Thus, during depression there may be a disruption in the normal relationship between the adrenergic receptor and its membrane environment.