Rocky Mountain (Sylvilagus nuttallii) and eastern (S. floridanus) cottontails were examined for their susceptibility to virulent and avirulent strains of the spotted fever agent, Rickettsia rickettsii. Both species of rabbits responded to inoculation of yolk sac suspensions containing 500 egg LD50 of either virulent or avirulent rickettsiae, with rickettsemias detectable as early as 3 days after inoculation and lasting up to 7 days. When fed upon by infected ticks, only one of three Rocky Mountain and one of four eastern cottontails developed rickettsemias detectable in embryonated hens' eggs. Rickettsial concentrations in the peripheral blood fo Rocky Mountain cottontails, infected either by syringe or by bites of one or more Dermacentor andersoni ticks harboring virulent R. rickettsii, were sufficient to infect simultaneously feeding normal larvae of this tick species. However, infection rates wre low and did not exceed 11.7%. In a single experiment, the bites of D. variabilis, infected with an avirulent strain of R. rickettsii, did not produce rickettsemias sufficient to infect normal D. variabilis larvae. These laboratory findings suggest that cottontail rabbits, although susceptible to R. rickettsii, do not serve as efficient reservoirs for infecting ticks.