Previous investigations have demonstrated a strain-associated differential susceptibility to herpes simplex virus-1 (HSV-1) infection in mice; C57BL/6 mice are more resistant to infection than BALB/c mice. Despite considerable research dealing with the immune response to HSV-1, relatively little attention has been paid to differences in immune responses between strains with different sensitivities to the virus. Here we report that immune responses (i.e., cytokine profiles, CTL activity, serum antibody, and natural killer cell activity) following footpad infection with a sublethal dose of HSV-1 do not substantially differ between the two strains. It is notable that C57BL/6 mice are also more resistant than BALB/c mice to other pathogens, including Leishmania, and this resistance is associated with a predominant TH1 response in C57BL/6 mice versus a predominant TH2 response in BALB/c mice. However, unlike several other pathogens, the increased susceptibility to HSV-1 infection of BALB/c mice, compared to C57BL/6 mice, does not appear to involve an obvious difference in the TH1 vs TH2 dominance of the immune response to this virus.