Schizophrenia shows substantial sex differences in age of onset, course, and treatment response, but the biological basis of these effects is incompletely understood. Here we show that during human development, males show a regionally specific decrease in brain expression similarity compared to females. The genes modulating this effect were significantly co-expressed with schizophrenia risk genes during prefrontal cortex brain development in the fetal period as well as during early adolescence. This suggests a genetic contribution to a mechanism through which developmental abnormalities manifest with psychosis during adolescence. It further supports sex differences in brain expression variability as a factor underlying the well-established sex differences in schizophrenia.