Parent-of-origin effect in transmission of bipolar disorder and abnormal phosphorus-31 magnetic resonance spectroscopy ( 31 P-MRS) findings in the brain in patients with bipolar disorder implicate pathophysiological role of mitochondrial DNA in bipolar disorder. The authors examined possible association of bipolar disorder with the 5178 polymorphism in mitochondrial DNA. Genotype frequencies of the 5178 polymorphism were examined by polymerase chain reaction-restriction fragment length polymorphism method in 145 patients with bipolar disorder and 184 controls. The rate of 5178C genotype was significantly higher in patients with bipolar disorder (81/125 (64.8%), P < 0.05) compared with controls (98/184 (53.2%)) when paternally transmitted cases were excluded. This effect was more prominent in patients with bipolar II disorder (5178C: 28/37, 75.6%, P < 0.02 to controls). Bipolar II patients with 5178A genotype without family history had significantly later age at onset (56.0 ยฑ 14.7 years, P < 0.05) than other bipolar patients. Brain intracellular pH measured by 31 P-MRS was significantly higher in bipolar patients with 5178A (7.04 ยฑ 0.03, n = 7, P < 0.05) than those with 5178C (7.00 ยฑ 0.03, n = 7). There was no difference of subcortical hyperintensity scores by magnetic resonance imaging between patients with 5178A and those with 5178C. These results suggest that the 5178 polymorphism in mitochondrial DNA may regulate vulner-ability to bipolar disorder via alteration of brain energy metabolism.