Objective: To evaluate the safety and efficacy of early rescue intracytoplasmic sperm injection (ICSI). Design: Retrospective cohort study. Setting: Teaching hospital. Patient(s): There were 13,232 ovarian stimulation cycles (IVF, n = 9,631; ICSI, n = 2,871; early rescue ICSI, n = 730) that resulted in the delivery of 5,001 babies (IVF, n = 3,670; ICSI, n = 1,095; early rescue ICSI, n = 246) from August 2008 to August 2013. Intervention(s): Early rescue ICSI. Main Outcome Measure(s): Clinical pregnancy rates, neonatal outcomes, and congenital birth defects were analyzed. Result(s): The early rescue ICSI cycles did not seem to have a negative effect on the clinical pregnancy rate (43.42%) when IVF cycles (45.33%) were compared with ICSI cycles (44.39%). In the early rescue ICSI group, a total of 254 clinical pregnancies were achieved: 197 (33.67%) live births, 38 (6.49%) miscarriages, 2 (0.79%) induced abortions, 3 (1.18%) fetal deaths, and 4 pregnancies (1.57%) without completion at follow-up. Overall, the multiple gestations, the delivery method, mean gestational age, preterm deliveries, mean birth weight, and rate of congenital birth defects of the early rescue ICSI group were similar to those in the conventional IVF and ICSI groups. Conclusion(s): Early rescue ICSI had similar clinical pregnancy rates when compared with conventional IVF and ICSI, in addition to the delivery of healthy children. The clinical evidence from the early rescue ICSI group did not show an elevated rate of malformations. Early rescue ICSI seems to be a safe alternative method for individuals with total fertilization failure or near total fertilization failure when compared with conventional IVF treatment. (C) 2015 by American Society for Reproductive Medicine.