Abstract: Objective To investigate the optimal ovulation induction with the combination of combining letrozole(LE)，clomiphene citrate (CC), and human menopausal gonadotropin (HMG) in polycystic ovary syndrome(PCOS) patients resistant to CC or LE. Methods Two hundreds nine PCOS patients (209 cycles) resistant to CC or LE were randomly divided into three groups: CC+HMG group (59 cycles), LE+HMG group (72 cycles) and LE+CC group (78 cycles). The patients in LE+CC group unable to form the dominant follicle after 54 cycles were enrolled into LE+CC+HMG group. Maximum follicle diameter (MFD), endometrial thickness, number of follicles (diameter＞1.4 cm), the level of serum estradiol (E2) were measured on the day of HMG administration. Also these results were observed and compared including the duration of treatment, dosage of HMG, number of ovulated follicles, clinical pregnancy rate, biochemical pregnancy rate, early abortion rate, twinning rate, and ectopic pregnancy rate. Results The ovulation rate was significantly lower in LE+CC group (30.77%) (P<0.05), but similar in the other three groups. The number of ＞1.4 cm follicles and ovulated follicles, ovulation duration and E2 concentration in LE+CC group were also at a lower level (P<0.05). The patients in LE+CC+HMG group showed higher E2 level and more HMG consumption (P<0.05). There was no statistical difference in endometrial thickness, MFD, clinical pregnancy rate, biochemical pregnancy rate, early abortion rate and twinning rate among these groups (P>0.05). No severe ovarian hyperstimulation syndrome (OHSS) or luteinized unruptured follicle (LUF) occurred. Conclusion Combintion of LE with CC could achieve 1/3 ovulation induction in PCOS resistant to CC or LE alone. When both combined with HMG, the induction of ovulation could be significantly higher than LE+HMG and CC+HMG, while the risk of multiple pregnancy and OHSS was reduced.