Many microbial pathogens have epitopes shared with host cell components and these epitopes may induce transient or longer-term tissue-damaging autoantibody responses. We observed that several mouse monoclonal antibodies (MAbs) raised against Orientia tsutsugamushi were also reactive with host cells. One such antibody, MAb Rb105, cross-reacted with the cytoskeleton, as shown by immunofluorescent staining. Biochemical studies identified the cross-reacting component as a cytokeratin protein. These results identify an epitope shared by O. tsutsugamushi and the cytokeratins of host cells. In addition, antibodies cross-reactive with the cytoskeleton were detected in the sera of scrub typhus patients, suggesting that an epitope similar to that detected by MAb Rb105 may be recognized by human antibodies.