Background: Thoracic aortic dissection (TAD) is the most common life-threatening disorder, and MMP-2 is involved in TAD pathogenesis. Our purpose is to systematically evaluate the association of the MMP-2 gene with TAD risk in Chinese Han population. Methods: In our case-control study, we recruited 755 unrelated participants: 315 case participants with TAD and 440 controls. Twenty-two tag SNPs were selected from MMP-2 gene and were genotyped. Genotype data were analyzed by logistic regression. Results: Although we did not find any significant association for MMP-2 SNPs using single-marker analysis, we identified many windows with haplotype frequencies significantly different between case participants and control participants using a variable-sized sliding-window strategy. In particular, the most significant association was shown by a 2-SNP window consisting of rs2241145 and rs9928731 (omnibus test: asymptotic P-asym = 7.48 x 10 (-5) and empirical P-emp = 0.001867). There were two protective haplotypes: CT (P-asym = 0.00303; odds ratio [OR], 0.403) and GC (P-asym = 0.000976; OR, 0.448). Conclusions: MMP-2 haplotypes are associated with genetic susceptibility to thoracic aortic dissection in Chinese Han population.