The ability of mice to resist infection with L. major correlated directly with the capacity of their LNC to produce TNF in response to in vitro parasite challenge. Blocking TNF in vivo by passively administering anti-TNF antibodies exacerbated the course of L. major infection, resulting in substantially larger cutaneous lesions and elevated numbers of parasites within those lesions. In addition, treatment of infected mice with exogenous rHuTNF afforded host protection as evidenced by smaller lesion size and decreased parasite counts. Taken together, these results suggest a central role for TNF in resistance to L. major.