Background: The purpose of this retrospective observational study was to identify prognostic factors that lead to a live birth (LB) in couples with unexplained infertility in order to define the best assisted-reproductive technique (ART) strategy. Methods: Prognostic factors of couples with unexplained infertility managed initially with gonadotropin intrauterine inseminations (IUI) at a single university fertility center were analyzed. Infertility was not considered "unexplained" in case of mild male infertility and suspicion of diminished ovarian reserve (FSH>10 IU/L). ART management consisted to start with IUI cycles and then, if failure, to propose in vitro fertilization (IVF). Couples were compared according to the results of IUI cycles in terms of LB. Results: Between January 2011 and July 2015, 133 couples with unexplained infertility were included (320 IUI cycles). The average age of women was 31.6±4.6 years and the average number of IUI per couple was 2.4±1.2. The IUI live birth rate (LBR) was 37.6%, with an average of 2 cycles to obtain a pregnancy. For 63 couples, no pregnancy occurred after IUI cycles. The prognostic factors of the two groups "LB after IUI" vs. "no LB after IUI" were not statistically different. The remaining 20 couples had a spontaneous pregnancy with a LB. Cumulative LBR, including spontaneous and ART pregnancies, was 65.7%. Of the 63 couples with no LB after IUI, 33.3% dropped-out from infertility treatments before starting IVF. Conclusions: To avoid couple's drop-out, we advise to start infertility treatment for unexplained infertility with two IUI before undergoing IVF if IUI failure.