Couples with unexplained infertility treated unsuccessfully with intrauterine insemination often receive further treatment with IVF or intracytoplasmic sperm injection (ICSI). The aim of this study was to evaluate the frequency of fertilization and fertilization failure with respect to the method of fertilization used, when half of the sibling oocytes were fertilized by conventional IVF and insemination and the remainder by ICSI. Included was the first IVF/ICSI treatment of 248 unexplained infertile couples who had failed to conceive after three IUI cycles. An overall pregnancy rate per embryo transfer of 57% was observed. A significantly better fertilization rate was obtained after ICSI as compared with IVF (68 versus 46%) (P < 0.005), and total fertilization failure following ICSI and IVF treatment was seen in 4.4 and 25% of the cycles respectively. The group who experienced total fertilization failure after IVF had normal semen parameters, although significantly lower sperm concentration and motility as compared with the entire study group. Transfer of their ICSI-fertilized oocytes subsequently resulted in a pregnancy rate of 49.2% per transfer. The policy of splitting the sibling oocytes can effectively minimize complete fertilization failure while maintaining high chances of achieving a pregnancy. At the same time, the optimal fertilization method for subsequent treatment cycles can be determined.