BACKGROUND: Mechanisms mediating immunity to malaria remain unclear, but animal data and experimental human vaccination models suggest a critical role for CD4 T cells. Advances in multiparametric flow-cytometry have revealed that the functional quality of pathogen-specific CD4 T cells, determines immune protection in many infectious models. Little is known about the functional characteristics of Plasmodium-specific CD4 responses in immune and non-immune individuals. METHODS: We compared T cell responses to P. falciparum among household-matched children and adults residing in high and low malaria transmission settings in Uganda. PBMCs were stimulated with P. falciparum antigen and IFNgamma, IL2, IL10 and TNFalpha production was analyzed via multiparametric flow cytometry. RESULTS: We found that the magnitude of CD4 responses was greater in areas of high transmission, but was similar between children and adults at each site. In high transmission settings, most P. falciparum-specific CD4 T cells in children produced IL10, while responses in adults were dominated by IFNgamma and TNFalpha. In contrast, in low transmission settings, responses in both children and adults were dominated by IFNgamma and TNFalpha. CONCLUSIONS: These findings highlight major differences in the CD4 response of immune adults and non-immune children that may be relevant for immune protection from malaria.