The destruction of infected cells by cytotxic T lymphocytes (CTL) is integral to the effective control of viral and bacterial diseases, and CTL function at large has long been regarded as a distinctive property of the CD8⁺T cell subset. In contrast, and despite their first description more than three decades ago, the precise contribution of cytotoxic CD4⁺T cells to the resolution of infectious diseases has remained a matter of debate. In particular, the CTL activity of pathogen-specific CD4⁺ “helper” T cells constitutes a single trait among a diverse array of other T cell functionalities, and overall appears considerably weaker than the cytolytic capacity of CD8⁺ effector T cells. Here, using an in vivo CTL assay, we report that cytotoxic CD4⁺T cells are readily generated against both viral and bacterial pathogens, and that the efficiency of MHC-II-restricted CD4⁺T cell killing adjusted for effector:target cell ratios, precise specificities and functional avidities is comparable in magnitude to that of CD8⁺T cells. In fact, the only difference between specific CD4⁺ and CD8⁺T cells pertains to the slightly delayed killing kinetics of the former demonstrating that potent CTL function is a cardinal property of both antiviral CD8⁺ and CD4⁺T cells.