Alterations in antioxidant status in schizophrenia suggest free radical-mediated neurotoxicity; this finding can be a consequence of increased free radical production. There are multiple pathways to excess free radical generation and subsequent oxidative stress. One such pathway is the formation of peroxynitrite by a reaction of nitric oxide (NO) and superoxide radical. NO is formed from L-arginine by nitric oxide synthase (NOS). A constitutive cytosolic isoform, neuronal NOS (nNOS), appears to be fairly stable in the postmortem brain tissues. Utilizing a sensitive fluorometric assay, NO levels were measured by its stable metabolites, nitrate and nitrite, in the caudate region of postmortem brain tissues from patients and control subjects. In the human brain, NO is metabolized primarily in the form of nitrate. A significantly increased level of NO was found in schizophrenia patients (241 +/- 146 pmol/mg dry weight, n = 18) than was found in those of normal (142 +/- 65 pmol/mg dry weight, n = 20) and psychiatric controls without schizophrenia (125 +/- 83 pmol/mg dry weight, n = 16) (analysis of covariance [ANCOVA], F = 6.446, df = 2,51, p = 0.003). These findings were independent of age, brain weight, postmortem interval (PMI), sample storage time, or cigarette smoking. Elevated NO levels in the brains of schizophrenia patients lend further support for the free radical pathology in schizophrenia.