The humoral and cell-mediated immune responses to the facultative intracellular pathogen Francisella tularensis were studied in subjects who had tularemia 25 years earlier. Serum agglutinin titers were low. Of 53 subjects, only 2 had a titer > 40. The F. tularensis-induced T cell response, on the other hand, was vigorous and in fact similar in magnitude to the response to purified protein derivative (PPD) of Mycobacterium tuberculosis. T cells from 44 of 52 subjects showed a significant (P < .05) proliferative response in vitro to each of four membrane proteins of F. tularensis. Only 2 subjects did not respond to any of the proteins. In most cultures from 18 subjects tested, interferon-gamma was produced in response to the proteins. During the last 25 years, tularemia has been reported only rarely in the region where the subjects lived, suggesting that an antigen-specific T cell response may persist after tularemia independently of reexposure to F. tularensis.