ABSTRACT: Antibodies to sperm head (ASA-H) are believed to impair reproduction, probably because of a reduction in fertilization of human oocytes. However, the incidence of ASA-H in couples with different etiologies of infertility undergoing in vitro fertilization/embryo transfer (IVF/ET) is unestablished. To examine this question, the semen, serum, and follicular fluid of 11 couples with unexplained infertility and 25 couples with tubal infertility undergoing IVF/ET were tested with the immunobead binding assay to identify ASA-H of IgA, IgG, and IgM isotypes. Comparing couples with unexplained vs. tubal infertility, 46% vs. 4% had ASA-H of at least one isotype in female serum (P = .006), 36% vs. 4% had ASA-H in follicular fluid (P = .023), 27% vs. 0% had ASA-H in semen (P = .023), and 18% vs. 4% had ASA-H in male serum (P = .022), respectively. ASA-H were present in one or more fluids tested in 55% of patients with unexplained infertility, compared to 8% of patients with tubal infertility (P = .005). Of the six women with ASA-H in their serum, 83% (5/6) were undergoing IVF/ET for unexplained infertility compared to 17% (1/6: P = .08) undergoing IVF/ET for tubal infertility. In summary, clinically significant ASA-H are present in a substantial number of infertile women undergoing IVF/ET, particularly those whose infertility is unexplained. Based on these findings, we conclude that it is efficacious to screen all women with unexplained infertility undergoing IVF/ET for ASA-H.