Abstract Background: A downregulation of I 2-imidazoline binding sites has been reported in frontal cortices of depressed suicide victims, according to I 2-radioligand binding and confirmed by Western blotting. We now report Western blots of imidazoline receptor proteins in hippocampi of subjects with and without depression at the time of death. Methods: Postmortem diagnoses were obtained from 17 cases of Axis I major depressive disorder and 17 cases without Axis I psychopathology. No psychotropic compounds were found in body fluids. Hippocampi were removed, sectioned, and assessed histologically. Throughout the analysis, each major depressive disorder sample was paired with a sample from a psychiatrically healthy subject based on equivalent life spans and postmortem delays. The antiserum was identical to that used in previous studies that reported a downregulation of cortical 29/30-kd imidazoline receptor–binding proteins in depression. Results: A triad of imidazoline receptor–binding protein bands (40–50 kd) was detected in the human hippocampus. Subjects with major depressive disorder had significantly less intensity in each imidazoline receptor–binding proteins band compared with control subjects ( p = .01 for overall bands). Conclusions: The present results can be aligned with previous reports of downregulation of I 2-radioligand binding sites in both cortices and platelets of depressed patients.