Two new heterodimeric sesquiterpenes, sterhirsutins A (1) and B (2), and two new sesquiterpenes, hirsutic acids D-E (3 and 4), were identified from the culture of Stereum hirsutum. The absolute configurations in 1 and 2 were confirmed by single-crystal X-ray diffraction experiments and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 are likely biosynthesized from a hirsutane-type sesquiterpene and α-humulene by a hetero-Diels-Alder cycloaddition. Compounds 1-4 showed cytotoxicity against K562 and HCT116 cell lines.