α-1-Antichymotrypsin (ACT) is a plasma protease inhibitor belonging to the serpine superfamily; it has many functions, and thus qualitative change in ACT is likely to result in specific diseases. We previously reported a variant AACT (ACT Isehara-1, Met389Val, A1252G) in patients with ischemic cerebrovascular disease (CVD). The present study was designed to examine the association of the variant with ischemic CVD, in 87 patients and 397 age-matched controls. We found that the frequency of the A1252G variant (ACT Isehara-1) was higher in the group with ischemic CVD than in the control group (P = 0.0397), which appeared to be independent of known risk factors. We subdivided the CVD group into lacunar and atherothrombotic subgroups. Further analysis by subtype of ischemic CVD showed an association of ACT Isehara-1 with lacunar infarction (P = 0.0036). These results suggest that ACT Isehara-1 is a new genetic risk factor for ischemic CVD, especially lacunar-type infarction, in Japan.