Altered accumulation and subcellular disposition of testicular Cd were examined as possible explanations for the resistance to Cd-induced testicular damage observed in certain inbred strains of mice. Mouse strains susceptible (129/J) or resistant (A/J) to Cd-induced testicular necrosis were injected iv with 10 or 45 mumol CdCl2/kg, respectively. This dosing regimen compensated for decreased Cd accumulation by A/J testes and established similar concentrations of Cd in testes of both strains (approximately 4 nmol Cd/g tissue). Twenty-four hours later, 129/J testes showed marked interstitial hemorrhage and seminiferous tubule necrosis, while A/J testes showed no microscopic evidence of damage. Two hours postinjection, no histopathologic changes were detected in testes of either strain; however, A/J testes had 15% more Cd associated with the cystosol than 129/J testes, and three times more Cd bound to a 14,500 MW cytosolic protein which had gel filtration and ion-exchange chromatography properties in common with metallothionein (MT). Therefore, resistance of A/J testes to Cd does not appear to be determined solely by decreased Cd accumulation, but is associated with increased binding of testicular Cd to a MT-like protein. However, this increase is not accompanied by a proportional increase in the total Cd-binding capacity of the MT-like protein in A/J testes compared to 129/J testes.