An independent cohort validated the association of change in psychosis with C4A. We provide evidence that genetic risk factors for schizophrenia from the xMHC region are associated with response to APDs and those variants significantly alter the imputed expression of C4A, HLA-C, and BTN3A2. The minor alleles predicting higher C4A level are associated with diminished improvement in psychotic symptoms after APD treatment. Here, C4A is linked to schizophrenia.