To determine whether the agent of human granulocytic ehrlichiosis (HGE) (Anaplasma phagocytophilum) may be maintained in a parallel enzootic cycle between cottontail rabbits and their ticks, we sampled these hosts from a zoonotic site during five transmission seasons. Evidence of infection was sought by microscopy and polymerase chain reaction from rabbit blood or splenic tissue, and from ticks collected from rabbits or from vegetation. Approximately 27% of all rabbits sampled contained evidence of active infection, and 66% were seropositive. The vectorial capacity of Ixodes dentatus was demonstrated by xenodiagnosis studies; in addition, 2% of host-seeking nymphs were infected. Haemaphysalis leporispalustris was not a competent vector. Because of their propensity to densely inhabit peridomestic sites, and because I. dentatus may be transported by birds, a parallel cycle of transmission in cottontail rabbits would facilitate introduction and perpetuation of the agent of HGE.