To study the anti-cancer effect of isoalantolactone, a sesquiterpene lactoneisolated from the roots of Inula heleniumon human gynecologic cancer cells. A structure-activity relationship experiment was designed to identify the functional moiety of isoalantolactone for its significant anti-cancer activity. Five gynecologic cancer cell lines were treated with isoalantolactone. Cell proliferation was determined by MTT assay in vitro and cell apoptosis by flow cytometry. We found isoalantolactone strongly inhibited the cell proliferationofHEC-1, HAC-2, HOC-21, and HeLa cells. Its inhibitory effect was comparable to that of well-known chemotherapeutic agents, cisplatin and taxol. Furthermore, isoalantolactone induced apoptosis in HeLa cells via caspase. On the contrary, its 11, 13-dihydro derivatives had much weaker anti-proliferative activities than the parent compound. Isoalantolactone exhibited strong anti-proliferative activities and apoptosis-inducing effects on gynecologic cancer cells. The 11, 13-dehydro lactone moiety was critical for its anti-proliferative activity. Copyright © 2020 Liu et al. Published by Tehran University of Medical Sciences.