OBJECTIVE: Matrix metalloproteinase-9 (MMP9) is a protease associated with degradation of collagen and elastin. Because increased MMP9 activity in vaginal tissue has been associated with pelvic organ prolapse (POP), we sought to comprehensively estimate MMP9 genetic variants and the risk for advanced prolapse. METHODS: This is a candidate gene association study of women with stage III-IV prolapse (case group, n=239) and women with stage 0-1 prolapse (control group, n=197). We attempted to oversample "extreme" phenotypes, including younger women with severe prolapse and older women without prolapse, in an attempt to concentrate the genetic effect. We used a linkage disequilibrium tagged approach to identify single nucleotide polymorphisms in MMP9 to evaluate in our study. To minimize potential confounding by race, our analysis focused on non-Hispanic white women. We performed multivariable logistic regression to estimate the association between MMP9 single nucleotide polymorphisms and case-control status, adjusting for age and vaginal parity. RESULTS: Women with advanced prolapse were slightly younger (64.8 ± 10.3 compared with 69.0 ± 10.2 years, P<.001) and more likely to have had one or more vaginal deliveries (96.6% compared with 82.2%, P<.001) when compared with control participants. Eight single nucleotide polymorphisms were assessed, which represented 93% coverage of the MMP9 gene. Of these, two were associated with advanced prolapse: 1) rs3918253 (adjusted odds ratio [OR] 0.64, 95% confidence interval [CI] 0.41-1.0, P=.05); and 2) rs3918256 (adjusted OR 0.64, 95% CI 0.41-1.01, P=.05). CONCLUSION: MMP9 is a biologically plausible candidate gene for POP given our results.