OBJECTIVE: Because glutamate carboxypeptidase II (GCPII) regulates both folate absorption and activation of N-methyl-d-aspartic acid receptors, the authors examined relationships between serum folate concentrations and clinical symptoms in schizophrenia patients. METHOD: For 91 outpatients with schizophrenia, clinical assessments were performed and serum folate, homocysteine, B12, glycine, and serine concentrations were measured. RESULTS: Serum folate concentrations were significantly lower than in a representative sample from the Framingham Offspring Study. Folate concentration correlated inversely with the Scale for Assessment of Negative Symptoms total score and was lower in patients with the deficit syndrome than in nondeficit patients. Homocysteine concentration correlated with the severity of extrapyramidal symptoms. CONCLUSIONS: These findings could reflect several possible mechanisms, including low dietary intake of folate, low GCPII activity, cigarette smoking, and the involvement of folate in the synthesis of neurotransmitters. Additional studies are needed to clarify these findings.