OBJECTIVE: To determine the optimum rescue time by comparison of results of rescue intracytoplasmic sperm injection (ICSI). STUDY DESIGN: A total of 112 couples of total fertilization failure, who had retrieved at least four mature oocytes, were prospectively randomized into two groups: the earlier rescue group, rescue ICSI performed between 4 and 6 hours after insemination, and the control group, rescue ICSI performed between 6 and 8 hours after insemination. RESULTS: There were no statistically significant differences in woman's age, duration of infertility, number of oocytes retrieved every cycle, and number of embryos transferred every cycle between the two groups. The normal fertilization rate of the earlier rescue group was increased compared with that of control group (63.1% vs. 55.7%, p < 0.05), whereas the abnormal fertilization rate in the earlier rescue group was decreased compared with control group (3.5% vs. 6.2%, p < 0.05). There was a trend suggesting an increase in the clinical pregnancy rate and implantation rate in the earlier rescue group compared with control group, though this failed to be significantly different. CONCLUSION: Rescue ICSI is an effective method of eliminating total fertilization failure. Rescue ICSI performed earlier could result in a better pregnancy rate in this select group of patients. (J Reprod Med 2011;56: 410-414)