Background: The study was designed to examine the relative contributions of genetic and nongenetic factors to structural brain abnormalities in schizophrenia and subjects at risk to develop the disorder. Methods: The brains of 15 monozygotic and 14 samesex dizygotic twins discordant for schizophrenia (patients) and 29 healthy twins pair-wise matched for zygosity, sex, age, and birth order were studied using high-resolution magnetic resonance imaging scans. Results: Intracranial and whole-brain corrected frontal lobe volumes were smaller (4.6% and 2.7%, respectively) in discordant monozygotic twins as compared with healthy monozygotic twins. Irrespective of zygosity, discordant twins had smaller whole-brain (2%), parahippocampal (9%), and hippocampal (8%) volumes than healthy twins. Moreover, patients had smaller whole-brain volumes (2.2%) than their nonschizophrenic cotwins, who in turn had smaller brains (1%) than healthy twins. Lateral and third-ventricle volumes were increased in discordant dizygotic twins as compared with healthy dizygotic twins (60.6% and 56.6%, respectively). Finally, within discordant twins, lateral ventricles were larger (14.4%) in patients than in their nonschizophrenic cotwins. Conclusions: Smaller intracranial volumes in the monozygotic patients and their cotwins suggest that increased genetic risk to develop schizophrenia is related to reduced brain growth early in life. The additional reduction in whole-brain volume found in the patients suggests that the manifestation of the disorder is related to (neurodegenerative) processes that are most likely nongenetic in origin.@en