In order to help prioritize the selection of candidate genes and to study possible trait and not state related changes in gene expression, we compared lymphocytic gene expression patterns of five individual family members with schizophrenia and nine unaffected individuals from a large multiplex high density pedigree. We screened gene expression by microarray consisting of 1128 brain focused genes. Three criteria for selection of microarray gene differences between schizophrenia and unaffected family members were employed: a significant t-test, expression in a majority of subjects, and fold change magnitude. Gene expression levels were significantly different for nine genes between individuals with schizophrenia compared to unaffected controls, and two genes were validated by real-time PCR. The expression of the neuropeptide Y receptor Y1 gene (NPY1R localized at 4q31.3-q32) and the human guanine nucleotide-binding regulatory protein Go-alpha (GNAO1 localized at 16q13) was significantly decreased in individuals with schizophrenia compared to unaffected family controls by microarray and real-time PCR. The cytosolic malate dehydrogenase gene (MDH1 localized at 2p13.3) was also significantly increased by microarray analysis and showed a trend for increase by real-time PCR. The significant genes are discussed in terms of proximity to linkage regions, prior association studies of schizophrenia, and other reports of microarray screening of schizophrenia tissue. Evidence from these studies taken together with the present study suggests critical pathways in schizophrenia may be studied in peripheral tissue as part of the strategy in functional genomic convergence. This preliminary study needs to be repeated by screening a larger set of genes in additional families with schizophrenia. The present study offers support for examination of gene expression patterns using lymphocytic RNA for complex neuropsychiatric disorders from large cohorts of patients.