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A method was developed to selectively deplete glutathione (GSH) in a single rat testis. Using intratesticular injections of a mixture of two GSH-depleting agents, diethylmaleate and buthionine sulfoximine, testicular GSH levels were decreased to 33-54% of control 2 hr after injection and remained suppressed for 24 hr. GSH levels in the contralateral testis and liver were not affected by this treatment. Comparisons between GSH-depleted and vehicle-injected (contralateral) testes, evaluated 2 weeks later, showed that although testis and epididymal weights and cauda epididymal sperm reserves were slightly reduced (to greater than or equal to 90% of controls), no changes were seen in testicular spermatid counts or in the morphology or motility of cauda epididymal sperm. An increase in histologically abnormal tubules localized to the injection site occurred in some GSH-depleted testes; however, the proportion of normal tubules containing step 19 spermatids was not affected. Thus, intratesticular injections of GSH-depleting agents selectively lowered GSH levels in the treated testis, with minimal adverse effects. This protocol can now be applied to investigate specific roles of GSH in the testes, particularly with regard to the possible modulation of the effects of testicular toxicants.