A quantitative transcriptomics analysis has reported that Calmodulin 1 (CALM1) is highly expressed in human brain tissues. This study aims to evaluate the relationship between CALM1 rs3179089 polymorphism and ischemic stroke (IS) in Chinese Han population. A total of 550 patients with IS and 550 control subjects were recruited and genotyped using Sequenom MassArray technology. The mRNA expression of CALM1 was measured using quantitative real-time polymerase chain reaction. CALM1 mRNA expression was significantly higher in patients with IS than that in control subjects (P = 0.006). The genomic frequency distribution was significantly different between female patients with IS and female controls (χ2 = 6.043, P = 0.047). In recessive model, CALM1 rs3179089 polymorphism was associated with the risk of IS in female patients. GG genotype significantly increased the risk of IS compared with the CC+GC genotype in females (OR 8.68, P = 0.042; adjusted OR 8.72, Padj = 0.042). Rs3179089 polymorphism was associated positively with plasmas D-Dimer of patients with IS in recessive model (βa = 3.24, P = 0.018; βb = 3.20, Padj = 0.019). Moreover, rs3179089 polymorphism was related positively to thrombin time of patients with IS in addictive (βa = 2.32, P = 0.005, βb = 2.26, Padj=0.006) and recessive model (βa = 11.19, P = 0.001, βb = 11.13, Padj = 0.001). CALM1 expression was involved in the development of IS. CALM1 rs3179089 polymorphism was associated with IS risk in Chinese females, and related to blood coagulation of IS patients.