Five new triterpenoids, irpeksins A-E (1-5), were isolated from fruiting bodies of the medicinal fungus Irpex lacteus. The structures as well as absolute configurations of the new compounds were established via extensive spectroscopic analysis, computational methods, and Cotton effects. Compounds 1-4 are featured by a scaffold of 1,10- seco- and ring B aromatic eburicane (24-methyllanostane), and compound 5 is characterized by a scaffold of 1,10-9,11- diseco- and ring B aromatic eburicane, which represents unprecedented cleavage patterns in the lanostane family. Compounds 1-5 showed significant inhibitory activity against NO production in LPS-activated RAW 264.7 macrophage cells with IC50 values varying from 2.2 to 19.6 μM.