Acne is the most common chronic inflammatory skin diseases. Multiple factors, such as hormonal, environmental, immunological, and genetic factors, are thought to be involved in acne. However, genetic studies have yet to elucidate the full mechanism of acne. The aim of this study was to investigate the association of MMP-2 (-1306C/T) and TIMP-2 (-418G/C) polymorphisms with the risk of acne vulgaris in a Chinese Han population. We also analyzed the correlation of clinical parameters and family history in patients with acne vulgaris. This study included 251 acne patients and 121 age- and sex-matched healthy controls. Genomic DNA was extracted from peripheral blood, and genotyping was performed by PCR and DNA sequencing techniques. There is a significant correlation between the MMP-2 (-1306C/T) polymorphism and the acne vulgaris (P<0.001). Although no association was found between the TIMP-2 (-418G/C) polymorphism and the acne vulgaris, patients with the MMP-2 CT/TIMP-2 GG or GC allele are at higher risk of acne vulgaris. There is also a significant difference in the severity of the disease between acne vulgaris patients with and without family history (P<0.001). This study indicated that the MMP-2 (-1306C/T) polymorphism, in combination with the TIMP-2 (-418G/C) polymorphism, contributes to acne vulgaris susceptibility in the Chinese Han population.