Background: To study the anti-cancer effect of isoalantolactone, a sesquiterpene lactoneisolated from the roots of Inula heleniumon human gynecologic cancer cells. Methods: A structure-activity relationship experiment was designed to identify the functional moiety of isoalan-tolactone for its significant anti-cancer activity. Five gynecologic cancer cell lines were treated with isoalantolac-tone. Cell proliferation was determined by MTT assay in vitro and cell apoptosis by flow cytometry. Results: 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. Conclusion: 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.