Diallyl sulfide (DAS), a flavor component of garlic that has been used as a food additive, exerts chemopreventive effects at several organ sites in rodents after administration of chemical carcinogens possibly by inhibiting carcinogen activation via cytochrome P450-mediated oxidative metabolism. In this study, we investigated the protective effect of DAS on the N-nitrosodimethylamine (NDMA)-induced immunosuppression of humoral and cellular responses in BALB/c mice and the possible mechanisms involved in this protection. We observed that oral administration of DAS prior to NDMA treatment for 14 consecutive days blocked the NDMA-induced suppression of the antibody response to a T-cell-dependent antigen, sheep erythrocytes, and the lymphoproliferative response to the T-cell and the B-cell mitogens in dose-dependent manners. Treatment of mice with DAS resulted in a significant decrease of cytochrome P450 2E1-dependent p-nitrophenol hydroxylase and NDMA demethylase activities. The results show that the protective effects of DAS against the NDMA-induced immunotoxicity may, at least in part, be due to its ability to block bioactivation of NDMA mainly by the inhibition of cytochrome P450 2E1.