The objective of this study was to assess if high total plasma homocysteine (tHcy) levels are a risk factor for severe leukoaraiosis (LA). This case-control study was done in a primary care neurology ward and included 178 consecutive patients. Patients with severe LA at CT scan were compared with patients without any LA regarding age, cerebrovascular risk factors, tHcy, vitamin B12, folate, creatinine levels and dementia. Multivariate logistic regression was used to find variables independently associated with severe LA. Age (odds ratio OR, 1.10 per year; p<0.0001), tHcy (OR, 1.07/micromol/l increase; p=0.045) and hypertension (OR, 2.97; p=0.007) were significantly associated with severe LA. Total homocysteine levels are associated with severe LA independently of other risk factors for cerebrovascular disease. This may suggest that decreasing tHcy may help preserve the integrity of the brain white matter.