Isoliquiritigenin (ILTG), a flavonoid group compound, exists in some foodstuffs and herbal medicines such as licorice (Glycyrrhiza uralensis Fisher). Previously, we showed that ILTG can suppress azoxymethane (AOM)-induced colon carcinogenesis in ddY mice. In the present report, we present evidence that ILTG markedly decreases both prostaglandin E2 (PGE2) and nitric oxide (NO) production in RAW264.7 mouse macrophage cells. The decrease of PGE2 was dependent on cyclooxygenase-2 (COX-2) expression and the decrease of NO appeared due to a decrease in inducible nitric oxide synthase (iNOS) protein expression. In mouse and human colon carcinoma cells, ILTG treatment suppressed cell growth and caused apoptosis. Furthermore, in vivo administration of ILTG inhibited the induction of preneoplastic aberrant crypt foci (ACF) in the male F344 rat colon. Our results suggest that ILTG is a promising chemopreventive agent against colon carcinogenesis.