As a part of a study to evaluate a formalin-killed Rickettsia rickettsii vaccine, lymphoproliferative (LT) and delayed-type hypersensitivity (DTH) skin test responses to killed R. rickettsii were measured as correlates of cell-mediated immunity in volunteers who were vaccinated, challenged with R. rickettsii, or both. We detected LT responses in 26 (51%) of 51 volunteers after vaccination. After challenge, six of six unvaccinated volunteers and 12 of 16 vaccinated volunteers developed Rocky Mountain spotted fever (RMSF); all 22 mounted LT responses. The vaccinated individuals developed LT responses of greater magnitude and 1-2 weeks earlier than unimmunized controls (41,049 versus 15,084 mean net counts per minute [cpm]), suggesting that vaccination primed the cellular immune system. Moreover, development of LT responses postvaccination was associated with the amelioration of RMSF, as indicated by a slightly longer mean incubation period (328 hr versus 302 hr) and a shorter illness (19 hr versus 26 hr) in LT responders than in LT nonresponders. However, the postvaccination LT response did not discriminate between vaccinated individuals who resisted challenge and those who did not. Skin tests using killed R. rickettsii as antigen, performed in volunteers 14-17 months postvaccination or 12-15 months after challenge, revealed a weak but significant reaction in 50% of those who had received vaccine only, and a moderately strong reaction in all vaccinated and unvaccinated volunteers who had been challenged with R. rickettsii. The relationships between induction of protective immunity against intracellular bacteria by killed and replicating organisms and LT and DTH responses are discussed.