LRH-1 is an orphan nuclear receptor predominantly expressed in tissues of endodermal origin, where it controls development and cholesterol homeostasis. We show here that LRH-1 induces cell proliferation through the concomitant induction of cyclin D1 and E1, an effect that is potentiated by its interaction with beta-catenin. Whereas beta-catenin coactivates LRH-1 on the cyclin E1 promoter, LRH-1 acts as a potent tissue-restricted coactivator of beta-catenin on the cyclin D1 promoter. The implication of LRH-1 in cell proliferation highlights an unanticipated crosstalk between LRH-1 and the beta-catenin/Tcf4 signaling pathway, which is relevant for the renewal of intestinal crypt cells.