To provide evidence-based recommendations to practicing physicians and others regarding the effectiveness and safety of therapies for unexplained infertility. ASRM conducted a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1968 through 2019. The ASRM Practice Committee and a task force of experts used available evidence and informal consensus to develop evidence-based guideline recommendations. Outcomes of interest included: live-birth rate, clinical pregnancy rate, implantation rate, fertilization rate, multiple pregnancy rate, dose of treatment, rate of ovarian hyperstimulation, abortion rate, and ectopic pregnancy rate. The literature search identified 88 relevant studies to inform the evidence base for this guideline. Evidence-based recommendations were developed for the following treatments for couples with unexplained infertility: natural cycle with intrauterine insemination (IUI); clomiphene citrate with intercourse; aromatase inhibitors with intercourse; gonadotropins with intercourse; clomiphene citrate with IUI; aromatase inhibitors with IUI; combination of clomiphene citrate or letrozole and gonadotropins (low dose and conventional dose) with IUI; low-dose gonadotropins with IUI; conventional-dose gonadotropins with IUI; timing of IUI; and in vitro fertilization and treatment paradigms. The treatment of unexplained infertility is by necessity empiric. For most couples, the best initial therapy is a course (typically 3 or 4 cycles) of ovarian stimulation with oral medications and intrauterine insemination (OS-IUI) followed by in vitro fertilization for those unsuccessful with OS-IUI treatments.