Epiregulin mediates LH ovulatory effects in vitro. This study evaluated the use of epiregulin as an alternative to hCG/epidermal growth factor (EGF) stimulus upon cultured ovarian follicles in contrast to isolated cumulus-oocyte complexes (COCs). Pre-antral mouse ovarian follicles were cultured for 12 days and final maturation was induced by administration of 0.65 nM EGF or 100 nM epiregulin without or with 1.2 IU/ml hCG. Results showed that both EGF or epiregulin as sole stimulators are poor inducers of mucification/expansion of cumulus cells and oocyte meiotic reinitiation in follicle-enclosed COCs (25±17 and 22±16% GVBD respectively; versus 97±4 and 90±15% GVBD by control hCG/EGF and hCG/epiregulin respectively; mean±S.D). Furthermore, EGF or epiregulin did not induce follicle luteinisation: progesterone production was marginally increased and oestradiol was incompletely shut down. Supposing that the sub-normal progesterone secretion was a potential cause for incomplete meiosis in this model, effectiveness of progesterone supplementation and addition of a progesterone receptor inhibitor (RU486) were evaluated on meiotic resumption. Progesterone was not found to be a major regulator of meiosis in this mouse model. Epiregulin induced meiosis more effectively in COCs isolated from cultured preovulatory follicles in a secondary culture well. In conclusion, epiregulin has similar effects as EGF upon fully grown follicles. Used as a sole stimulator of periovulatory events in intact cultured follicles, both are poor inducers of follicle luteinisation and oocyte maturation. By contrast, epiregulin is as efficient as hCG/EGF, when used as meiotic stimulator for COCs isolated from the follicular environment (mural granulosa and theca cells; and conditioned medium). © 2009 Society for Reproduction and Fertility.