Gonadotropin-releasing hormone agonist (GnRH-a) therapy is frequently applied to reduce the volume of uterine leiomyomas (UL). In addition, the possible relationship between mast cells (MC) within UL and the development of UL has been suggested, but the role of MC in UL remains to be determined. UL with or without GnRH-a therapy in 121 premenopausal patients were reviewed. The number of MC was evaluated between the two groups, immunohistochemistry was done for insulin-like growth factor-I (IGF-I), and the association between the IGF-I immunoreactivity in UL and the GnRH-a therapy was analyzed. The number of MC significantly increased in UL in GnRH-a therapy, while IGF-I immunoreactivity was significantly reduced in smooth muscle cells of these UL. Furthermore, IGF-I immunoreactivity in MC was inversely correlated with the size reduction rate of UL in GnRH-a therapy. Although GnRH-a therapy is considered to reduce the size of UL transiently, the regression of UL was in part hampered by the increased IGF-I secretion from the increased MC after GnRH-a therapy. Therefore, the more the IGF-I secretion from MC in UL increases, the less effective the GnRH-a therapy is on the size reduction of UL. Thus, the present study may provide an explanation of the possible mechanism of GnRH-a resistance in UL.