Schizophrenia is associated with deficits in working memory, a cognitive function that depends on the connections of the prefrontal cortex (PFC) with the thalamus and other cortical regions. Pyramidal neurons in PFC deep layer 3 play a central role in both thalamocortical and corticocortical circuitry. Given that somal size tends to be associated with both the dendritic and axonal architecture of a neuron, abnormalities in these circuits in schizophrenia may be associated with a change in the somal size of deep layer 3 pyramidal neurons. We used design-based stereology to estimate the somal volume of pyramidal neurons in deep layer 3 of PFC area 9 in 28 subjects with schizophrenia, each of whom was matched to 1 normal comparison subject for sex, age, and postmortem interval. The geometric mean of the somal volume estimates in the subjects with schizophrenia was significantly (P =.02) decreased by 9.2%. This decrease was associated with a shift in the distribution of somal volumes toward smaller sizes. Neither antipsychotic medication treatment history nor duration of illness was associated with somal size. These findings independently replicate previous reports of decreased somal size in the PFC in schizophrenia. The reduction in size of deep layer 3 pyramidal neurons is consistent with abnormalities in thalamocortical and corticocortical circuitry, suggesting that disruption of these circuits may contribute to cognitive abnormalities in schizophrenia.