Control of the intracellular parasites that cause malaria and visceral leishmaniasis (VL) is dependent on the generation of pro-inflammatory, IFNγ+ Tbet+ CD4+ T (Th1) cells by infected hosts. Immunoregulatory IL-10 produced by Th1 cells serves to mitigate subsequent inflammation and related disease pathology. However, these IL-10-producing Th1 (Tr1) cells can also not only promote parasite persistence, but may impair immunity to re-infection and potential vaccine efficacy. Here, we identify molecular and phenotypic signatures that distinguish Th1 cells from Tr1 cells in both experimental VL, caused by infection of C57BL/6 mice with the human parasite Leishmania donovani, and in Plasmodium falciparum-infected humans participating in controlled human malaria infection (CHMI) studies. Such characterisations allow for the better understanding of Tr1 cell development and function in the context of these parasitic diseases, and for the identification of targets for immune modulation to improve anti-parasitic immunity.