Background and Purpose - Silent brain infarcts (SBI) and white matter lesions are relatively common neuroimaging findings, especially in the elderly population. The genetic background for SBI and white matter lesions in a large Japanese general population was investigated. Methods - Subjects were recruited from participants in the National Institute for Longevity Sciences, Longitudinal Study of Aging. Genotyping of methylenetetrahydrofolate reductase ( MTHFR) C677T gene mutation and brain MRI examination were performed in 1721 subjects free of any history of stroke. SBI and white matter lesions were diagnosed from MRI findings. Results - Of 1721 MRI examinations, SBI was observed in 178 ( 10.3%). The prevalence of SBI and white matter lesions increased with age. The prevalence of SBI was significantly higher in subjects with the MTHFR TT genotype compared with the TC + CC genotype (14.6% versus 9.5%; 42 of 288 versus 136 of 1433; chi(2) = 6.71; P = 0.010). The stage of white matter lesions was not significantly different. In subjects greater than or equal to60 years of age (n = 849), the prevalence of SBI was significantly higher in TT than TC + CC (27.7% versus 16.6%; 36 of 130 versus 119 of 719; chi(2) = 9.16; P = 0.002). The prevalence of moderately advanced white matter lesions was also significantly higher in TT than TC + CC ( 60.7% versus 49.0%; 79 of 130 versus 352 of 719; chi(2) = 9.16; P = 0.002). After correction for other risk factors, the MTHFR TT genotype was independently associated with SBI ( odds ratio [ OR], 1.72; 95% CI, 1.10 to 2.68; P = 0.018) and moderately advanced white matter lesions ( OR, 1.58; 95% CI, 1.07 to 2.33; P = 0.02). Conclusions - These findings indicate that the MTHFR TT genotype is an independent risk factor for SBI and white matter lesions in the general Japanese population, especially in elderly subjects.