The US Army successfully developed a live-attenuated Venezuelan Equine Encephalitis (VEE) vaccine, TC-83, in 1961, and subsequently developed a formalin-inactivated vaccine, C-84, in 1974. Initial evaluation of both vaccines was promising, but no long-term safety and immunogenicity data have been reported This study is the first analysis of the long-term safety and immunogenicity of TC-83 and C-84. From January 1976 to December 1990, 821 laboratory workers at the USAMRIID were vaccinated with a single 0.5 mi subcutaneous (s.c.) dose of TC-83; 128 were boosted with a single 0.5 mi s.c. dose of C-84. Eighty-two per cent of vaccinees responded to TC-83 with an 80% plaque reduction neutralization titer (PRNT(80)) of greater than or equal to 1:20. Minor side-effects were noted in 23% of vaccinees. No long-term sequelae were recorded. Kaplan-Meier analysis showed a 60% probability of vaccinees maintaining a PRNT(80) of greater than or equal to 1:20 for 5.5-8 years. C-84 was given to two groups: 76 initial nonresponders to TC-83, Group A, and 52 initial responders to TC-83 whose PRNT(80) became <1:20 over time, Group B. C-84 successfully boosted 76% of Group A and 100% of Group B to a PRNT(80)greater than or equal to 1:20. Kaplan -Meier analysis showed 100% probability of Group B members maintaining a titer of greater than or equal to 1:20 for the duration of follow-up, which, in some cases, exceeded 10 years; while Group A had only a 60% probability of maintaining a titer for 1-2 years. Only minor local reactions to C-84 were noted in 6.3% of vaccinees. We conclude that, although TC-83 is reactogenic, when administered as the primary vaccine and C-84 is administered as a boost, these vaccines provide good long-term immunity and are safe in humans. However, a single dose vaccine that is more immunogenic and less reactogenic is needed. Copyright (C) 1996 Published by Elsevier Science Ltd.