CONTEXT: Elevated prenatal homocysteine level is a plausible risk factor for schizophrenia because of its partial antagonism of N-methyl-D-aspartate receptors under physiologic glycine concentrations and its association with abnormal placental function and pregnancy complications. OBJECTIVE: We examined whether elevated maternal levels of homocysteine during the third trimester were associated with adult schizophrenia risk. DESIGN: Nested case-control study of a large birth cohort, born from 1959 through 1967 and followed up for schizophrenia from 1981 through 1997. SETTING: Population-based birth cohort and health plan. PARTICIPANTS: Cases (n = 63) were diagnosed with schizophrenia and other spectrum disorders (mostly schizophrenia and schizoaffective disorder). Controls (n = 122) belonged to the birth cohort; had not been diagnosed with a schizophrenia spectrum or major affective disorder; and were matched to cases on date of birth, sex, length of time in the cohort, and availability of maternal serum samples. MAIN MEASURES: Archived maternal serum samples were assayed for homocysteine levels during pregnancies of cases and matched controls. RESULTS: In a model that tested for a threshold effect of third-trimester homocysteine levels, an elevated homocysteine level was associated with a greater than 2-fold statistically significant increase in schizophrenia risk (odds ratio, 2.39; 95% confidence interval, 1.18-4.81; P = .02). CONCLUSIONS: These findings indicate that elevated third-trimester homocysteine levels may be a risk factor for schizophrenia. Elevated third-trimester homocysteine levels may elevate schizophrenia risk through developmental effects on brain structure and function and/or through subtle damage to the placental vasculature that compromises oxygen delivery to the fetus. If future studies both replicate this association and support a causal link, then the use of folic acid supplementation would merit evaluation as a strategy for prevention of schizophrenia in offspring.