Background and Purpose—Homocysteine is associated with stroke, but it is not clear whether this relationship is causal. We examined the association between total serum homocysteine concentration (tHcy) and cerebral infarction in a cohort of Finnish male smokers.Methods—This is a matched case-control study of 201 cases of cerebral infarction and 201 concurrently sampled age-matched controls nested in a cohort of 13 840 male smokers free of cardiovascular disease at the completion of the Alpha-Tocopherol and Beta-Carotene (ATBC) Cancer Prevention study. Conditional logistic regression was used to calculate odds ratios (ORs) and to adjust for confounding variables. An unmatched analysis was also performed.Results—The geometric mean tHcy was 13.3 &mgr;mol/L (95% CI, 12.6 to 13.9) in cases and 12.6 &mgr;mol/L (95% CI, 12.0 to 13.2) in controls (P=0.09). There was a graded increase in the OR of cerebral infarction per quartile increase in tHcy (OR, 1.0, 1.7, 1.9, 2.1; trendP=0.02; 201 case-control pairs) when adjusted for traditional risk factors. There was a similar trend in a subgroup of 120 case-control pairs for which further adjustment for lifestyle factors was possible (OR, 1.0, 1.9, 2.5, 2.2; trendP=0.07 in the matched analyses; OR, 1.0, 1.2, 1.9, 2.0; trendP=0.02 in the unmatched analyses). The adjusted OR per 1-SD increase in log-transformed tHcy (equivalent to 4.7 &mgr;mol) was 1.4 (95% CI, 1.1 to 1.7;P=0.01).Conclusions—tHcy appears to predict cerebral infarction in Finnish male smokers.