Smoothelin is a specific type of cytoskeletal protein found in smooth muscle cells (SMCs). Several previous research studies have examined the relationship between smoothelin and atherosclerotic plaque. The aim of the present study was to further assess the association between the human SMTN gene and cerebral infarction (CI) using a haplotype-based case-control study. A total of 168 CI patients and 259 supercontrols were genotyped for the five single-nucleotide polymorphisms (SNPs) used as genetic markers for the human SMTN gene (rs2074738, rs5997872, rs56095120, rs9621187 and rs10304). Data were analyzed for three separate groups that included total subjects, men and women. The genotypic distribution of rs10304 for men showed a significant difference between the control and CI groups. In addition, the frequency of the C-T-T-A haplotype (established by rs5997872, rs56095120, rs9621187 and rs10304) was significantly higher in the CI versus the control group (p = 0.013), while the frequency of the C-A-T-G haplotype (established by rs5997872, rs56095120, rs9621187 and rs10304) in the CI group was significantly lower than that seen in the controls (p = 0.021). In conclusion, we confirmed that the haplotype constructed using rs5997872, rs56095120, rs9621187 and rs10304 was a useful genetic marker of CI in Japanese men.