Ecologists are beginning to recognize the potential importance of interactions between parasites as drivers of infectious disease dynamics. Increasing evidence suggests that the effects of immunologically-mediated interactions between dissimilar parasites occupying very different niches within a host can affect population-level patterns of disease. Helminths are widespread macroparasites of wildlife, now recognized as having the potential for regulating host populations. We investigated the effects of helminths (GI nematodes) on bovine tuberculosis (TB) susceptibility in free-ranging African buffalo (Syncerus caffer). We expected that as a consequence of immunological cross-regulation between the T helper cell 1 (Th1) and T helper cell 2 (Th2) pathways of the immune system, nematode infection would influence host susceptibility to TB, with important consequences for TB transmission dynamics. Our results show that individuals with lower nematode burdens were more likely to be infected with TB. Among TB-negatives, nematode fecal egg count was positively and significantly correlated with a measure of Th1 immune function (interferon gamma, IFNg), suggesting that ability to resist nematode infection impairs immunity against intracellular parasites. A significant interactive effect of nematode fecal egg count, eosinophil count (index of Th2 function) and body condition on IFNg in TB-positives further suggests that nematodes may also influence TB progression. These observational results were corroborated by experimental evidence demonstrating that nematode removal via anthelminthic treatment results in an increased Th1 response and improved body condition. We conclude that nematodes can influence TB susceptibility, and use a two-parasite, one-host disease model and comparative analyses to explore the effects of nematode presence on TB invasion success and microparasite distributions.