The lipolytic enzyme hepatic lipase (HL) may facilitate mobilization of cholesterol substrate for ovarian steroidogenesis. We investigated whether HL was necessary for optimum reproduction in the female mouse by analyzing breeding performance and ovarian responses to gonadotropins in HL−/− mice. HL−/− female mice bred with HL−/− males had the same pregnancy success rate and pup survival rate as did wild-type (WT) mice but had significantly smaller litters, producing 1.7 fewer pups per litter. Mice were primed with eCG/hCG, and at 6 h post-hCG the HL−/− mice had smaller ovaries than did the WT mice. HL deficiency specifically affected ovarian weight; adrenal gland weights did not differ between WT and HL−/− mice. HL−/− mice weighed more than age-matched WT mice. Between the two mouse genotypes, uterine weights were the same, indicating that estrogen production was equivalent. However, the HL−/− ovaries produced significantly less progesterone than did the WT ovaries within 6 h of hCG stimulation. HL−/− ovaries had the same number of large antral follicles as did the WT ovaries but had fewer hemorrhagic sites, which represent ovulations, fewer corpora lutea, and more oocytes trapped in corpora lutea. We suggest that reduced progesterone synthesis following hCG stimulation attenuated the final maturation of preovulatory follicles, resulting in smaller ovaries. Furthermore, reduced progesterone production limited the expression of proteolytic enzymes needed for tissue remodeling, resulting in fewer ovulations with a corresponding increase in trapped or unovulated oocytes and providing a possible explanation for the smaller litter size observed in spontaneously ovulating HL−/− mice.