1. An assay was developed using sucrose gradient purified platelet plasma membranes which allowed detection, for the first time in patients, of both super-high affinity (KD = 17 pM) and high affinity (KD = 1.7 nM) binding sites. 2. Limited Scatchard plot analyses were performed on platelet membranes from depressed patients and controls using 10 pM-2.5 nM 3H-p-aminoclonidine (3H-PAC). 3. Patients (n = 9) were age-paired with healthy control subjects for simultaneous blood drawing, platelet preparation and analysis. 4. All patients were endogenous depressives with Hamilton-Depression scores ranging from 19 to 30 at the time of pre-treatment. Seven of the nine patients were analyzed again at six weeks of treatment with antidepressant medication. 5. Using 60 pM 3H-PAC (a concentration determined to bind predominantly to the super-high affinity receptor state) pre-treatment patient values were higher then paired controls (p = 0.06). Post-treatment analysis of seven of the patients and paired controls showed no differences (p = 0.5) suggesting a normalization of receptor binding following treatment. 6. No differences were observed in platelet yield or morphology or in the percent of other blood cell contaminants in the platelet preparations between patients at pre-treatment and controls. However, the platelet yield was significantly lower in patients post-treatment (p = 0.06). 7. These results are in agreement with two previous studies showing elevated 3H-clonidine binding to high affinity sites from depressed patients. The data presented herein suggest that there is a modest 1.25-fold elevated super-high affinity platelet adrenoceptor binding in depressed patients pre-treatment. Receptor binding becomes normal post-treatment.