OBJECTIVES: Insulin-like growth factor I (IGF-I) and other components of the IGF system have been implicated in the etiology of several human malignancies. We have undertaken a case-control study among Greek women to explore the relation of major components of the IGF system (IGF-I, IGF-II and IGF-binding protein 3, IGFBP-3) with endometrial cancer risk. METHODS: During a 1-year period (1999), 84 incident cases of histologically confirmed endometrial cancer were compared with 84 control women admitted to the same clinical department for small gynecological operations, mainly pelvic prolapse. Data were modeled through multiple logistic regression. RESULTS: Endometrial cancer was positively associated with IGF-II and inversely with IGF-I. Both associations were statistically significant and they appear symmetrical around the null value. IGFBP-3 is positively associated with endometrial cancer risk, but this association does not reach statistical significance. CONCLUSIONS: This study adds to the gradually developing consensus that components of the IGF system play a central role in human carcinogenesis. It is possible that IGF-II, rather than IGF-I, is closely linked to the etiology of endometrial cancer, the form of cancer most strongly associated with obesity.