A prospective longitudinal study to examine the relationship between cellular immune responses to the synthetic malarial peptide SPf66 and malaria infection and morbidity was carried out in 187 children aged 0.5-15 years in the Wosera area of Papua New Guinea. Cellular responses were assessed by proliferation and stimulation of cytokines representing the Th1 and Th2 cell subsets (interferon gamma [IFN gamma] and interleukin-4 [IL-4]. Most children (66%) did not respond to SPf66 by any measure. Among the responders, the highest response was obtained for IL-4 (19%) followed by IFN gamma (10%), and the least for proliferation (5%). Analyses of the relation of T cell response to malaria infection showed that the IFN gamma response to SPf66 was positively correlated with parasite density (r = 0.27, P = 0.001). There was no association between the cellular response to SPf66 and concurrent or subsequent malaria morbidity, whichever clinical definition was used. Thus none of these cellular immune responses predicted efficacy of SPf66 in this highly endemic area.