The skin response in guinea pigs at various times after immunization with epididymal sperm in Freund's complete adjuvant is reported. Findings were correlated with the progression of the autoimmune orchitis. Also, possible skin reactivity to sperm extract at 8 months after bilateral vasectomies in which both ends of the vasa had been ligated was investigated. The histological changes in the testes at 5 months postvasectomy were studied. Epididymal sperm was obtained by flushing out the vas and epididymis of mature guinea pigs. The dried epididymal sperm was used for immunization, dissolved or suspended in PBS. For skin testing, a heat-treated extract of the sperm (BES) was used. The methods of preparing reagents is described. The skin reactions to BES and to a purified protein derivative (PPD) in females were similar to those of any standard protein antigen. In males, this reaction resembled that in females at 1 week after immunization but later was different. Induration and erythema were greater in females (p less than .001) from 2 weeks on. The response of males to PPD was less than in females at 1 week but at 2 weeks was the same. Males immunized with purified ovalbumin responded to PPD similarly to females. After 8 months, following vasectomy, the response to BES at 24 hours was similar to that of controls. Testes weighed at 1 week after immunization were increased, possibly due to edema, but after the 3rd week weight was decreased. Histology of the testes after immunization showed cellular infiltration after 2 weeks and disappearance of spermatogenic elements from the seminiferous tubules. Evidence of delayed hypersensitivity to sperm was not shown.