Stroke is a serious cardiovascular disease and is also the leading cause of long-term disability in developing and developed countries. Because matrix metalloproteinase-9 (MMP-9) is associated with the risk of many cardiovascular diseases, we investigated the relationship between single nucleotide polymorphisms (SNPs) in MMP-9 and the risk of Ischemic stroke (IS) in a southern Chinese Han population. This study included 250 stroke patients and 250 healthy controls. Genotyping was performed using the Agena MassARRAY system, and chi-squared tests and genetic models were used to evaluate the associations between MMP-9 SNPs and the risk of IS. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusted for age. Polymorphism rs3787268 was associated with increased the risk of IS. Specifically, the genotype "G/A" significantly correlated with IS risk in the co-dominant model odds ratio (OR) = 1.62; 95% confidence interval (CI) = 1.10-2.41; p = 0.035), while genotypes "G/A" and "A/A" may increase the risk of IS based on the dominant model (OR = 1.62; 95% CI = 1.12-2.35; p = 0.0097). This SNP was also significantly associated with IS risk in the log-additive model (OR = 1.33; 95% CI = 1.03-1.70; p = 0.026). Conversely, haplotype "C/G" appears to reduce the risk of IS (OR = 0.71; 95% CI = 0.54-0.95; p = 0.019). Our study showed that the rs3787268 locus in the MMP-9 gene may increase risk of IS in a southern Chinese Han population and thus provide insight into the IS pathogenesis.