Plasmodium falciparum histidine-rich protein 2 (PfHRP-2) is a water-soluble protein released from parasitized erythrocytes into in vitro culture supernatants. This study sought to determine whether PfHRP-2 could be detected in the plasma of humans with P. falciparum malaria. A monoclonal antibody (1E1) is described that binds to PfHRP-2. By using monoclonal antibody 1E1, PfHRP-2 was identified by Western blot (immunoblot) analysis in the plasma of 37 of 39 (95%) patients experiencing either a first or repeat episodes of P. falciparum malaria and by dot blot analysis in the plasma of 40 of 41 patients tested. PfHRP-2 was not detected in 30 control, uninfected subjects. The current demonstration of PfHRP-2 in plasma, plus the fact that it is a structurally well-characterized molecule present in all natural isolates of P. falciparum tested, makes PfHRP-2 of interest for its potential effects on the host immune system and as an antigen for specific diagnosis of malaria.