The cellular response within lesions and in draining lymph was examined in sheep following a primary intracutaneous injection of live or killed S. aureus. Microscopic examination of sections from live S. aureus lesions (12, 24, 48, and 96 h following vaccination) revealed a high ratio of neutrophils to macrophages at all times. This ratio was initially high following inoculation of killed S. aureus but decreased steadily at successive sampling times. Representative sections from lesions were subjected to indirect immunofluorescent staining to identify IgM-, IgG1-, and IgG2-containing cells. The ratio of IgG2- to IgG1-containing cells in lesions produced following live S. aureus vaccination was significantly greater than the ratio in lesions produced by killed staphylococci. Lesions induced by live S. aureus recruited significantly greater numbers of 51Cr-labeled allogeneic neutrophils from blood than did lesions induced by killed S. aureus. During the first 6 h this difference was approx. 20-fold. The volume of lymph and the number of leukocytes draining live S. aureus lesions was considerably greater than from lesions produced by killed staphylococci. The proportion of neutrophils in lymph draining both types of lesions increased markedly during the first two days of the response but was observed to be greater and remained higher for a longer period of time in lymph draining vaccine lesions produced following injection of live staphylococci. The increase in proportion of neutrophils in lymph was accompanied by a concomitant decrease in proportion of lymphocytes and macrophages. No immunoglobulin-containing cells or anti-staphylococcal antibody production was detected in lymph draining either type of lesion. These differences in inflammatory responses may contribute to the documented differences in immune responses to live and killed staphylococcal vaccines.