Tumor necrosis factor-  (TNF- ) is suggested to play multiple roles in immune and pathologic responses in tuberculosis. In this study, we have developed a system for the expression of recombinant guinea pig TNF-  (rgpTNF- ). Using rgpTNF-  along with neutralizing anti-rgpTNF-  antiserum, we tested the effect of modulating the levels of TNF-  on antigen-specific T cell proliferation in splenocytes. By neutralizing TNF-  in the supernatant of PPD-pulsed splenocytes with anti-rgpTNF- , we observed hyperproliferation. Conversely, the addition of rgpTNF-  resulted in a significant suppression of PPD-induced lymphoproliferation. In addition, when unvaccinated and BCG-vaccinated guinea pigs were treated with polyclonal rgpTNF-  antiserum throughout the first 3 weeks following low-dose, pulmonary infection with Mycobacterium tuberculosis H37Rv, we observed splenomegaly in BCG-vaccinated guinea pigs. We also detected higher levels of splenic granuloma organization in the non-vaccinated group as well as a significant number of plasma cells associated with granulomata from the BCG-vaccinated group. These results suggest that modulating the availability of TNF-  in BCG-vaccinated guinea pigs can lead to immuno-dysregulation and, perhaps, the inappropriate enhancement of humoral immunity. Conversely, abrogating TNF-  activity in the context of a hyperinflammatory response in non-vaccinated guinea pigs may, in fact, rescue them from immunopathological consequences of overproducing TNF- .