Nitric oxide (NO) is a neurotransmitter that acts as a second messenger of the N-methyl-D-aspartate receptor and interacts with the dopaminergic and the serotonergic systems. NO involvement in pathological processes relevant to neuropsychiatric disorders stems from its ability to modulate certain forms of synaptic plasticity, and from its capacity to be transformed to a highly active free radical. Additionally, multiple links have been reported between the NO-producing enzyme, nitric oxide synthase (NOS) 1, and both schizophrenia and bipolar disorder (BPD). RNA and DNA isolated from dorsolateral-prefrontal cortices of schizophrenia patients, bipolar patients and controls (n = 26, 30 and 29, respectively) were donated by the Stanley Foundation Brain Collection. Gene expression was measured by Real-Time-PCR. Genetic polymorphisms were genotyped by restriction-fragment length-polymorphism analysis, and by product-size determination of PCR products amplified with a fluorescent primer.Expression analysis of pan-NOS1, as well as of 2 of its isoforms, "NOS1_1d" and "NOS1_1f", which differ in their first exons and translational strength, revealed a trend for pan-NOS1 over-expression (P = 0.075) in schizophrenia patients (1.33-fold), and significant over-expression (P < 0.05) of NOS1_1d and NOS1_1f in this group (1.54-fold and 1.61-fold, respectively). No expressional alteration was observed in BPD. Polymorphisms at the promoters of NOS1_1d and NOS1_1f, previously shown to be functional in vitro, revealed no significant allelic or genotypic differences among clinical groups and showed no effect on these transcripts' expression. In conclusion, understanding the molecular mechanisms underlying the over-expression of specific NOS1 isoforms, which is unique to schizophrenia, may assist in identifying targets for new drugs.