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Vinylcyclohexene diepoxide (VCD) produces ovarian toxicity in female mice and rats, whereas testicular damage occurs only in mice. The objectives of these studies were to determine the target cell(s) and spermatogonial survival following VCD administration. In addition, the effects of 4-vinylcyclohexene (VCH) and two epoxide metabolites, vinylcyclohexene 1,2-monoepoxide and VCD were compared. Male mice were dosed daily with VCD (320 mg/kg/d, i.p.) and killed at 5, 10, 15, 20, 25, or 30 d. Two groups were dosed daily for 30 d and allowed to recover for 30 or 60 d. Decreases in testis weight began at 5 d and continued to 30 d. These decreases corresponded to progressive necrosis of germ cells. After 5 d of VCD, there was loss of Type I and B spermatogonia in Stages II to VI and of preleptotene spermatocytes in Stages VI to VIII. After 30 d of dosing, seminiferous tubules were devoid of germ cells except for spermatogonial stem cells. Following 30 d of recovery, 100% of the seminiferous tubules were repopulated. Epididymal spermatozoa were present after 60 d of recovery. Increasing doses of VCD (0 to 320 mg/kg/d) resulted in increasing testicular toxicity. Neither VCH (800 mg/kg, i.p.) nor VCM (200 mg/kg, i.p.) caused testicular damage. VCD administration initially results in destruction of spermatogonia and spermatocytes, which are undergoing DNA synthesis and cell replication, followed by loss of maturing cells. Neither VCH nor VCM caused testicular germ cell destruction, although all three compounds destroy germ cells in female mice. Therefore, further investigation will be necessary to understand these differences in chemical-induced toxicity between ovaries and testes.