Liver receptor homolog 1 (LRH-1) is an orphan nuclear receptor that synergizes with beta-catenin/T cell factor 4 signaling to stimulate intestinal crypt cell renewal. We evaluated here the impact of haploinsufficiency of LRH-1 on intestinal tumorigenesis by using two independent mouse models of human colon tumorigenesis. Haploinsufficiency of LRH-1 blunts intestinal tumorigenesis in the ApcMin/+ mice, a genetic model of intestinal cancer. Likewise, Lrh-1+/- mice are protected against the formation of aberrant crypt foci in the colon of mice exposed to the carcinogen azoxymethane. LRH-1 gene expression is reduced in tumors that express elevated levels of the proinflammatory cytokine TNF-alpha. Reciprocally, decreased LRH-1 expression in Lrh-1+/- mice attenuates TNF-alpha expression. Compared with normal human colon, expression and subcellular localization of LRH-1 is significantly altered in neoplastic colon. In combination, these data suggest a role of LRH-1 in the initiation of intestinal tumorigenesis both by affecting cell cycle control as well as through its impact on inflammatory pathways.