OBJECTIVE: Schizophrenia may involve the two cerebral hemispheres differentially. This study was conducted to determine whether left and right hippocampal neuronal size, shape, and orientation are normally asymmetrical or asymmetrically affected in schizophrenia. METHOD: The authors examined postmortem tissue from the left and right hippocampus of 17 normal individuals and 14 individuals with schizophrenia. They measured the size, shape, and variability in orientation of pyramidal neurons in hippocampal subfields CA1-CA4 and the subiculum in computer images of 10-micron coronal sections stained with cresyl violet. RESULTS: Both neuronal size and shape showed significant effects of diagnosis and a three-way interaction between diagnosis, hemisphere, and subfield. Neurons of the schizophrenic subjects were smaller than those of the normal subjects in the left CA1, left CA2, and right CA3 subfields; their shape differed from that of the normal subjects in the left CA1, left subiculum, and right CA3 subfields. There were no group differences in variability of neuronal orientation, but neurons in the CA3 genu in the schizophrenic subjects were less variable on the right than on the left. In the normal subjects, except for larger neurons in the left than in the right CA2 subfield and some left-right differences in variability of neuronal orientation, no statistically significant asymmetries were observed. CONCLUSIONS: The data confirm that hippocampal neuronal size is decreased in schizophrenia and reveal that the shape of neurons is altered, supporting the view that hippocampal cytoarchitectural abnormalities may be part of the cerebral substrate of schizophrenia. They also provide further evidence that the abnormalities are localized and lateralized.