The mechanism for resistance to ectromelia infection has been investigated in B6 and B10 congenic strains of mice which carry different alleles at the H-2 major histocompatibility locus. Greater susceptibility in some B10 congenic strains of mice has been associated with higher viral titres in the draining popliteal and inguinal lymph nodes as well as spleen at 3 days post infection. T cells which develop cytotoxic function following in vitro culture in the presence of T cell growth factors have also been detected in the popliteal lymph nodes of B6/B10 congenic strains of mice as early as 3 days post infection. Greater cytotoxicity has been detected in cultures of cells from resistant B6/B10 mice than from the susceptible B10 congenic strain B10.G, or other semi-resistant B10 congenic strains which differ at the H-2 locus. The early activation of T cells appears to be under H-2 gene control and activated T cells may play an "early" role in controlling viral replication within the lymphoid system.