Immunodepletion studies of P-4-vaccinated mice indicate that CD4+ and not CD8+ T cells are critical for protection against Leishmania pifanoi (Leishmania mexicana complex). Although a moderate CD8+ T-cell response is elicited by vaccination, CD4+ T cells are the dominant responding population in vitro and at the cutaneous site of infection. These protective T cells produce gamma interferon (IFN-gamma), macrophage migration inhibitory factor (MIF), and tumor necrosis factor/lymphotoxin (TNF/LT), each of which significantly contributed to intracellular parasite destruction in vitro. These results indicate that a singular CD4+ T-cell response (IFN-gamma, MIF, and/or LT/TNF) can provide protection against New World cutaneous leishmaniasis.