Although immunological tests based on the detection of histidine-rich protein 2 (HRP2) from the parasites permit the rapid diagnosis of Plasmodium falciparum malaria, such tests are not yet sufficiently sensitive to detect every bloodsmear-positive case. Some individuals infected with P. falciparum may appear test-negative because of the presence of anti-HRP2 antibodies in their sera. A longitudinal follow-up of HRP2 antigenaemia and antibody responses to this antigen has now been conducted in a group of 45, bloodsmear-positive malaria cases of various ages, both during acute infection with P. falciparum and after antimalarial treatment. Pre-treatment, 'day-0' samples of fingerprick blood were tested for HRP2 (in antigen-capture ELISA) and for antigen-specific IgM and IgG (in indirect ELISA). The patients were then treated, with standard doses of chloroquine, before being retested, for HRP2 and anti-HRP2 antibodies, on days 7, 15 and 28. The level of antigenaemia, which on day 0 was found to be positively correlated with parasitaemia (r = 0.741; P < 0.001), had only fallen by an insignificant amount by day 7 but showed further, significant falls between days 7 and 15 (P < 0.001) and between days 15 and 28 (P < 0.01). Although no significant relationship was observed between the blood concentrations of HRP2 and anti-HRP2 IgM or IgG on days 0 or 7, the level of HRP2 antigenaemia was found to be positively correlated with the concurrent titre of anti-HRP2 IgM on day 15 (r = 0.612; P < 0.001) and day 28 (r = 0.501; P < 0.001). The titres of HRP2-specific IgG gradually increased over the 28 days of follow-up but were not found to be significantly correlated with the decreasing levels of HRP2 antigenaemia. When the 45 day-0 samples of blood were tested for HRP2 in a rapid diagnostic test (RDT), three appeared negative, probably because of interference from the circulating, free, anti-HRP2 antibodies in the plasma. The three RDT-negative samples were significantly different from the 42 RDT-positive, having relatively low HRP2 antigenaemias (P < 0.001) and relatively high titres of anti-HRP2 IgM (P < 0.05) and IgG (P < 0.001). Control samples of blood, from four patients infected with P. vivax and five healthy, normal individuals, were considered ELISA-negative for HRP2 and anti-HRP2 IgM or IgG. It appears that, during human infection with P. falciparum, serum levels of HRP2 antigen remain elevated for at least 7 days post-treatment, despite the host's development of antigen-specific immune responses both before and after treatment.