Background: Abnormalities of cortical neuronal organization and reductions in neuronal somal size have been reported in schizophrenia. The purpose of this investigation was to assess patterns of neuronal and glial distribution in the anterior cingulate cortex (ACC) in major depressive disorder (MDD), schizophrenia, bipolar disorder (BPD), and normal control subjects (15 subjects per group). Methods: Estimates for neuronal somal and glial nuclear size and density were obtained. We employed two-dimensional morphometric analysis to examine the location of neurons and glia in a 1000-mum-wide strip of cortex. Results: A decreased clustering of neurons was seen in BPD (p = .001). No other group differences were observed in the clustering of neurons, glia, or of neurons about glia. Neuronal somal-size was reduced in layer 5 in schizophrenia (18%, p = .001), BPD (16%, p < .001), and MDD (9%, p = .01). Neuronal density was increased in layer 6 in BPD (63%, p = .004) and schizophrenia (61%, p = .006) and in layer 5 in MDD (24%, p = .018) and schizophrenia (33%, p = .003). Conclusions: The results of this study indicate that reduced neuronal somal size and increased neuronal density in cortical layers 5 and 6 of the A CC may be key features of schizophrenia, MDD, and BPD.