Because of evidence from genetic linkage and genome-wide association studies, as well as suggested involvement of infection, the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1 has been implicated in the development of schizophrenia.Here, we investigated how gene variants across the MHC region are associated with brain structure in a large ethnically homogenous sample (n = 420), including patients with schizophrenia spectrum disorders and other severe mental illness and healthy control subjects.We demonstrate highly significant associations between common gene markers in the MHC region and cerebral ventricular volume specifically in schizophrenia spectrum patients (uncorrected p values between 1.16 × 10 −4 and 2.00 × 10 −7 ). One single nucleotide polymorphism, rs2596532, survives Bonferroni correction for multiple testing across all single nucleotide polymorphisms and brain structure measures (adjusted p value 5.59 × 10 −4 ).The results indicate that MHC variants are implicated in characteristic brain abnormalities of schizophrenia.