With the introduction of intracytoplasmic sperm injection (ICSI), couples with severe male factor infertility have been able to achieve fertilization and clinical pregnancy rates comparable to other in vitro fertilization patients. However, despite the utilization of microsurgical sperm injection techniques, failure of fertilization still occurs in a few patients. How such fertilization failure after ICSI might impact later ICSI treatments is less understood. We report a case of total fertilization failure after ICSI using sperm from a normozoospermic husband of a patient with unexplained infertility. Six months after the cancelled cycle, the couple conceived naturally. Unfortunately, it was an ectopic pregnancy, which required laparoscopy and surgical removal of the right fallopian tube. This case shows that a failed ICSI cycle, therefore, does not imply a hopeless prognosis for future ICSI treatment. Moreover, in cases with unexplained ICSI failure, natural conception can subsequently occur. The aim of this study is two-fold: to discuss a rare case of a spontaneous pregnancy after total fertilization failure with ICSI and to develop counseling material for patients and doctors who are faced with such a rare situation. To our knowledge, this is the first report of a case of spontaneous pregnancy after total fertilization failure with ICSI.