AbstractCommon principles can be discerned in the response of the epididymis to vasectomy, despite species differences. Increases in the size and number of lysosomes are the most frequent changes in the epididymal epithelium. The presence or absence of additional alterations such as changes in the height of the epithelium may be related to variations in distensibility of the vas deferens and epididymis. Direct measurements by micropuncture of epididymal and seminiferous tubule hydrostatic pressure indicate that, contrary to dogma, increased pressure in the distal epididymis after vasectomy is not generally transmitted to the seminiferous tubules. The epididymal interstitium shows microscopic changes indicative of chronic inflammation, with infiltration of macrophages, lymphocytes, and plasma cells, and rats with these lesions have higher antisperm antibody levels than animals lacking epididymal changes. Macrophages and neutrophils may enter the duct through the epididymal epithelium, at sites of rupture of the duct, and in the efferent ductules. Cyst‐like spermatic granulomas occur in virtually all species where the epididymis or vas deferens ruptures with escape of spermatozoa. The sites and timing of granuloma formation may depend on the mechanical properties of the tract in different species, and they are probably important in the immune response to vasectomy. Postvasectomy sera in Lewis rats recognize a consensus repertoire of dominant autoantigens that closely resembles the antigens bound by sera from rats immunized with isologous spermatozoa. There are multiple routes for disposal of the sperm that continue to be produced after vasectomy. © 1995 Wiley‐Liss,