OBJECTIVES: To determine the impact of Plasmodium falciparum malaria coinfection and its treatment on cellular reservoirs of viral replication in HIV-1-infected persons and to relate this to changes in systemic immune activation. METHODS: Plasma samples were obtained from HIV-1-infected individuals (n = 10) at diagnosis of acute malaria, 4 weeks after parasite clearance and from HIV-infected aparasitemic controls (n = 10). Immunomagnetic HIV-1 capture analysis was used to determine the cellular origin of cell-free virus particles present in all 30 plasma samples and indices of immune activation were measured using enzyme-linked immunosorbent assays. RESULTS: Compared with controls, the detectable proportion of HIV-1 particles derived from CD14 macrophages and CD26 lymphocytes was increased in persons with acute malaria coinfection and correlated with markedly increased plasma concentrations of both proinflammatory cytokines and soluble markers of macrophage and lymphocyte activation. Parasite clearance following treatment with antimalarial drugs resulted in decreased detection of HIV-1 particles derived from the CD14 macrophage cell subset and correlated with a marked diminution in systemic immune activation. CONCLUSIONS: Acute P. falciparum malaria coinfection impacts virus-host dynamics in HIV-1-infected persons at the cellular level, notably showing a reversible induction of HIV-1 replication in CD14 macrophages that is associated with changes in immune activation.