- Objective: Previous studies have found elevated plasma homocysteine levels in schizophrenic patients. This study examined homocysteine levels in euthymic bipolar patients. Methods: Homocysteine levels in 41 euthymic outpatients with bipolar disorder (DSM IV) were compared with 305 comparison subjects from a large employee health screening program. Homocysteine levels were assessed using high-pressure liquid chromatography by fluorescence detection following labeling of homocysteine with monobromobimane. Functional deterioration in patients was rated as ‘present’ or ‘absent’ by consensus of two treating clinicians. Results: Data were analyzed by two-way (sex, patient versus control) ANCOVA, with age as the covariant. Significant effects were found for age (p < 0.001) and for sex (p < 0.001) and a significant two-way interaction was found for group by sex (p < 0.001). One-way (by group) ANCOVAs were then performed separately for each sex. For the male subjects, a main effect was found for group (p = 0.001) and for age (p < 0.001): young male bipolar patients have higher homocysteine levels than controls. Among the females, bipolar patients had homocysteine levels, which were lower than controls across all age groups (p < 0.05) with homocysteine levels increasing with age for both groups (p < 0.001). ANCOVA, which divided subjects into three groups – bipolar patients with and without functional deterioration versus comparison subjects – found a significant group by sex interaction (p < 0.05). Sheffe’post-hoc comparisons revealed that among the male subjects, bipolar patients showing deterioration had homocysteine levels which were significantly higher than those of comparison subjects, while bipolar subjects without deterioration had homocysteine levels which were almost identical to the comparison subjects. Conclusion: Bipolar patients who show functional deterioration have plasma levels of homocysteine, which are significantly elevated as compared with controls.