Objective: The study endeavored to observe the effects of estrogen and progestin on expression of matrixmetalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in a nude mouse model of endometriosis (EMT) and to explore the roles of MMP-2/TIMP-2 in the pathogenesis of EMT. Methods: Sixty nude mice were injected in the abdominopelvic cavity with human endometrial tissue and randomly divided into four hormone treatment groups (estrogen, progestin, estrogen+progestin, and saline control; n = 15 per group). Implantation rates and gross morphological characteristics were assessed. Further, expression of MMP-2 and TIMP-2 in ectopic endometrial lesions was detected by immunohistochemistry. Results: The overall implantation rate of endometrial samples was 87.5% (50/60) in injected nude mice. Although there was no statistically significant difference in implantation rates between groups, the number of lesions in the progestin group was higher than that in other groups, and the size of lesions in the progestin and estrogen+progestin groups was larger than in the estrogen and control groups (p < 0.05). Further, expression levels of MMP-2 in the estrogen and estrogen+progestin groups were higher than in the progestin and control groups (p < 0.05). In contrast, expression levels of TIMP-2 in estrogen, progestin, and estrogen+progestin groups were lower than in the control group; additionally, the expression level of TIMP-2 in the progestin group was lower than in the estrogen group (p < 0.05). Finally, the ratios of MMP-2/TIMP-2 expression in the estrogen, progestin, and estrogen+progestin groups were higher than for the control group; in fact, this ratio was highest in the estrogen+progestin group (p < 0.05). Conclusions: The nude mouse is an appropriate model for early clinical studies of EMT, specifically in the detection of MMP-2 and TIMP-2. These proteins appear important in the pathogenesis of EMT. Specifically, estrogen can raise the expression level of MMP-2 to promote ectopic implantation of endometrial tissue. Meanwhile, progestin can inhibit the expression of TIMP-2 to raise the MMP-2/TIMP-2 ratio, which can enhance invasiveness of ectopic endometrium to promote implantation.