Estrogen and estrogen receptors are known to play important roles in the pathophysiology of pelvic organ prolapse (POP). We investigated whether estrogen receptor alpha (ERalpha) gene polymorphisms were associated with POP risk by conducting a case-control association study in 88 women with POP and 153 women without POP. Genotypes of the ERalpha (ESR1) gene polymorphisms (rs17847075, rs2207647, rs2234693, rs3798577, and rs2228480) were determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis. There was significant difference between women with and those without POP in the distribution of the ESR1 rs2228480 genotypes evaluated. By using multivariable logistic regression, age and ESR1 rs2228480 genotype GA were significantly associated with POP risk. Although the sample size of women with POP studied is small, the present study shows that ERalpha genotype may be associated with POP risk.