Infertility is commonly associated with cystic fibrosis (CF). Although infertility in men with CF has been thoroughly investigated, the infertility observed in women with CF has not been well studied. To investigate female infertility associated with CF, we used two independently derived mouse models of CF. Both of these models displayed decreased fertility characterized by a reduction in litter number and litter size. Our findings suggest that much of the reduced fertility in these mice originates from decreased fertilization due to inadequate sperm transport within the female reproductive tract. However, our data indicate that additional reproductive phenotypes in the CF female mice also contribute to the reduced fertility including small ovarian and uterine size, aberrant estrous cycles, and decreased oocyte ovulation rates. These data, along with previous work demonstrating that the gene mutated in CF, the cystic fibrosis transmembrane conductance regulator (CFTR), is normally expressed in tissues vital to reproduction, raises the possibility that CFTR may have a direct effect on fertility. If so, CFTR may also play an important role in normal female fertility within the general population.