Objective: To determine an optimal insemination technique in patients undergoing IVF after failed IUI and the role of intracytoplasmic sperm injection (ICSI) in such cases. Design: Prospective, randomized study in couples with unexplained infertility (n = 63) and mild endometriosis (n = 7) undergoing IVF after four failed TUI cycles. Sibling oocytes were randomized into standard IVF or ICSI insemination according to the order of retrieval. Setting: In vitro fertilization program at the Institute Valenciano de Infertilidad, Valencia, Italy. Patient(s): Seventy couples with unexplained infertility undergoing NF after failing to conceive with controlled ovarian stimulation and IUI. Intervention(s): In vitro fertilization and ICSI. Main Outcome Measure(s): Fertilization, cleavage, and embryo quality were compared in IVF- and ICSI-inseminated oocytes. Result(s): There was no significant difference in fertilization rates between ICSI (60.4%) and conventional NF (54.0%). Similarly, there was no difference in embryo quality between both groups. There was no total fertilization failure in ICSI-inseminated oocytes, whereas 8 (11.4%) of 70 cases showed absence of fertilization when conventional IVF was used. Conclusion(s): Couples with unexplained infertility and mild endometriosis failing to conceive with IUI and undergoing IVF have an 11.4% chance of fertilization failure that can be overcome easily by using ICSI in at least some oocytes. ICSI, however, is not superior to IVF as an insemination technique in most cases. These data should be used in counseling patients. (C) 1997 by American Society for Reproductive Medicine.