In view of the well known species differences in the sensitivity of pancreatic B-cells to the toxic glucose analogue alloxan, it was tested whether spermatozoa from two species with a different diabetogenic effect of alloxan displayed a similar difference in their sensitivity to this drug. In canine spermatozoa, less than 2 mM alloxan profoundly reduced the rate of glucose oxidation and cellular motility whereas more than 5 mM was required to significantly alter these parameters in human spermatozoa. Such species difference was not observed in spermatozoal sensitivity towards the inhibitory effects of tert-butyl hydroperoxide. The phenomenon is not attributable to a different rate of alloxan uptake since the drug is not incorporated by dog or human spermatozoa. The alloxan toxicity was counteracted by D-glucose and its 3-O-methyl analogue in both species, and was potentiated by ascorbic acid; however, only in man. The protective effect of D-glucose was much less marked in tert-butyl hydroperoxide-cytotoxicity. It is concluded that the observed species difference in spermatozoal alloxan sensitivity is not related to differences in alloxan uptake or in sensitivity to organic peroxides; differences in cellular scavenging of superoxide anion radicals and/or ascorbic acid metabolism may explain the lower sensitivity of human spermatozoa for alloxan.