Soon after a patient from Tennessee died of Rocky Mountain spotted fever (RMSF), several family members developed symptoms suggestive of the disease and were treated presumptively for RMSF. Fifty-four persons visiting the index patient's home were interviewed; serum samples were collected from 35. Three additional cases of RMSF were confirmed, all of which occurred in first-degree relatives. Time spent at the family home and going into the surrounding woods were significantly associated with developing antibodies to Rickettsia rickettsii. Ticks were collected and examined for rickettsiae by polymerase chain reaction analysis. Because hyperendemic foci and family clusters of RMSF can occur, when a case is suspected clinicians should be vigilant for signs and symptoms consistent with R. rickettsii infection in other persons who may have been similarly exposed.