Purpose: To review the clinical importance of including the hypo-osmotic swelling (HOS) test in routine male fertility testing which in general is not evaluated by most physicians dealing with infertility. Materials and Methods: Pregnancy rates were evaluated in patients with low HOS test scores. A low HOS test was specifically defined as having less than 50% of sperm exhibiting the normal physiologic response of tail swelling, when subjected to a hypo-osmolar solution. Pregnancy rates of patients with low HOS test were examined after intercourse, intrauterine insemination (IUI), conventional oocyte insemination, and in vitro fertilization (IVF). Patients with a low HOS test were also treated with a protein digestive enzyme chymotrypsin. Patients receiving intervention then underwent IUI, IVF with conventional oocyte insemination, or IVF with intracytoplasmic sperm injection (ICSI). Pregnancy rates of the cohort receiving intervention were then examined for comparison. Results: The HOS test abnormality leads to normal fertilization but almost invariably negatively effects embryo implantation. Treatment with chymotrypsin, or performing IVF with ICSI, can overcome the toxic protein causing the embryo implantation defect. This toxic protein may be cryolabile and freezing sperm or embryos may prove to be another mode of therapy. Conclusions: The HOS abnormality may be the most reliable semen abnormality predicting failure to conceive even with IVF unless the defect is negated. Therapy is very effective. Unfortunately this test is rarely evaluated by most infertility specialists but it should be. The frequency increases with age.