Macrophage activation during acute falciparum malaria in 71 Thai adults was investigated by measuring urinary neopterin and serum interferon-gamma (IFN-gamma). Neopterin, a product of IFN-gamma-activated macrophages, was elevated in 94% of patients upon admission (day 0, prior to treatment) and in all at some time during the period of study. Neopterin levels tended to rise further (days 1-5) before falling back towards the normal range as patients recovered following effective chemotherapy (days 6-8). IFN-gamma was measured in 32 patients and found to be directly related to neopterin concentration. Both neopterin and IFN-gamma values were highest in patients experiencing a first malaria infection. Among those with histories of prior malaria, neopterin and IFN-gamma levels were inversely related to the number of previous infections. Morbidity, as assessed by degree and duration of fever, was directly related to neopterin concentration. This longitudinal study quantitatively describes the extent and duration of macrophage activation in falciparum malaria. The data also suggest that with repeated malaria infection and antigen exposure, there is a progressive decrease or possibly suppression of the T cell-macrophage interaction mediated by IFN-gamma.