This chapter provides an overview on immunological causes of male factor infertility. From a clinical standpoint, determining the site(s) of infection and/or inflammation is a key first step. Identifying causative organisms and providing appropriate medical treatment, including antibiotics and anti-inflammatory agents, are mainstays of therapy. The chapter presents specific sites of inflammation and infection within the male reproductive tract, characterizing each to provide a framework for arriving at the proper diagnosis, treatment, and counseling options for the affected patient. Some of the sites of inflammation include urethra, prostate, seminal vesicles, and vas deferens. Leukocytes initiate and maintain a complex series of steps in the immune system response. Nitric oxide is purported mediator of leukocyte damage to sperm. More specific testing for seminal leukocytes includes Bryan-Leishman staining, peroxidase (Endtz) test, and monoclonal antibodies directed against leukocyte surface molecules.