Background. The mechanisms responsible for altered T-cell responses and cytokine production after injury are not well understood. We used T-cell receptor (TCR) transgenic mice to study burn injury effects on naive versus antigen-activated CD4+ T cells in vivo. Methods. One week after sham or burn injury, lymph node cells were prepared from TCR transgenic mice and stimulated with TCR transgene-specific antigens. T-cell proliferation was measured and culture supernatants were tested for interleukin-2 (IL-2), interferon-γ (IFN-γ), IL-4, and IL-10 by enzyme-linked immunosorbent assay (ELISA). Burn injury effects on antigen-activated T cells were studied by immunizing TCR transgenic or wild-type mice at the time of injury. Results. The antigen-stimulated proliferation of naive CD4+ T cells was unaffected by burn injury and no increase in T-helper 2 (Th2)-type cytokine production was observed. Instead, burn injury augmented IFN-γ production by naive CD4+ transgenic T cells, and IL-2 production was marginally reduced. Thus, burn injury primed naive T cells for an enhanced Th1-type response. In contrast, antigen-specific protiferation, IL-2, and IFN-γ production by T cells harvested from immunized wild-type mice were suppressed. Unexpectedly, high mortality was observed when burn-injured TCR transgenic mice were immunized. Conclusion. Our results show that burn injury has differential effects on naive and antigen-activated CD4+ T cells and can prime naive CD4+ T cells.