Abstract The platelet membrane was used as a model system to examine α 2-adrenergic receptors in 30 depressed patients and 30 healthy control subjects. The number of binding sites and their affinity for 3H-UK 14304 (5-bromo-6-(2-imidazoline-2-ylamino)-quinoxaline), a potent, highly selective α 2-adrenergic receptor agonist, was measured. Plasma magnesium and free 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were assayed in the same sample. A decreased agonist-receptor affinity was found in depressed patients, whereas receptor density was not significantly altered compared with that in control subjects. In bipolar depressed and dysthymic patients, there was a tendency toward a higher density of α 2-adrenergic receptors. This trend was not apparent in unipolar, recurrent depressed subjects. Moreover, a positive correlation between B max and K d values was observed in patients but not in control subjects—a finding that suggests that a compensatory phenomenon occurs in depression. After the patients were treated with antidepressant drugs, an increased affinity (decrease in K d) was observed, together with a decrease in binding sites. Plasma magnesium concentrations were higher in drug-free depressed patients than in control subjects. In addition, magnesium concentrations were negatively correlated with the density of α 2-adrenergic receptor binding sites in depressed patients, both before and during treatment. Lastly, a trend toward a negative correlation between plasma MHPG concentration and the number of binding sites was also observed. These results suggest a complex multifactorial regulation of α 2-adrenergic receptors, which are probably hyposensitive in depressive syndromes.