In an attempt to reduce the number of couples whose basic infertility evaluation fails to reveal any abnormality, 57 couples with the diagnosis of unexplained infertility were further investigated by ultrasound monitoring for folliculogenesis, sperm antibody testing, hamster egg penetration assay, and major histocompatibility (human leukocyte antigen) typing. The use of these techniques allowed the diagnosis of luteinized unruptured follicle in 5% (three patients), sperm antibodies in 5% (three patients), low sperm penetration in 11% (six patients), and human leukocyte antigen-B locus homozygosity in 37% (21 couples). When the incidence of B locus homozygosity among the 57 couples with unexplained infertility was compared with that in 51 fertile couples, the difference was significant at p = 0.025. Thus by adding the diagnostic tools of ultrasound monitoring of folliculogenesis, sperm antibody testing, hamster egg penetration assay, and major histocompatibility antigen typing, the diagnosis of unexplained infertility can be reduced by 60%.