Dendritic cells (DC) can represent an important target for vaccine development against viral infections. Here, we studied whether interferon-gamma (IFN-gamma) could improve the functions of DC and analyzed human red blood cells (RBC) as a delivery system for Tat protein. Monocyte-derived DC were cultured in human serum and matured with monocyte-conditioned medium (MCM) in the presence or not of IFN-gamma. Tat was conjugated to RBC (RBC-Tat) through avidin-biotin bridges. Stimulation of DC with IFN-gamma increased the release of interleukin (IL)-12 and tumor necrosis factor-alpha and inhibited the production of IL-10. Moreover, IFN-gamma-treated DC up-regulated the release of CXCL10 (IP-10) markedly and reduced the secretion of CCL17 TARC significantly, attracting preferentially T-helper (Th)1 and Th2 cells, respectively. DC internalized RBC-Tat efficiently. Compared with DC pulsed with soluble Tat, DC incubated with RBC-Tat elicited specific CD4+ and CD8+ T-cell responses at a much lower antigen dose. DC matured in the presence of MCM were more effective than immature DC in inducing T-cell proliferation and IFN-gamma release. Finally, immature and mature DC exposed to IFN-gamma were better stimulators of allogeneic T cells and induced a higher IFN-gamma production from Tat-specific CD4+ and CD8+ T lymphocytes. In conclusion, erythrocytes appear an effective tool for antigen delivery into DC, and IFN-gamma could be used advantageously for augmenting the ability of DC to induce type 1 immune responses.