•  Mice display greater susceptibility to infections with maximum parasites loads and lesion sizes at week six post-infection. •  At weeks 2 and 4 post-infection, the IFN-γ secretion is lower, while the IL-4, IL-10, and IL-13 secretion were higher by L. major lysate-stimulated lymphocytes. •  At early time points after infection, the Th1/Th2 balance is diverted toward Th2 cells. •  Protective immunologic memory is not impaired in EBI3−/− mice. •  IL-27 is essential for early control of parasite replication. The gene discussed is IL13; the disease is infection.