Immunoglobulin isolated from the sera of individuals living in a malarious area of Papua New Guinea was tested for an effect on the growth in vitro of four isolates of Plasmodium falciparum, three from Papua New Guinea and one from Thailand. The Papua New Guinea isolates were inhibited to the same degree by individual immunoglobulin preparations, and inhibition varied from 0 to 98% (assessed by a radioisotopic readout). Immunoglobulin preparations which inhibited the Papua New Guinea isolates caused less inhibition of the Thai parasites. Biosynthetically labeled parasite proteins were analyzed by two-dimensional gel electrophoresis, and differences were detected in the protein and antigenic composition of isolates which differed in their sensitivity to inhibitory immunoglobulin. Three acidic proteins (Mr 200,000, 150,000, and 65,000) were found only in the Papua New Guinea isolates. All Papua New Guinea isolates contained a high-molecular-weight basic protein with an Mr of 220,000 (Pf220), but the corresponding protein of the same molecular weight in the Thai isolate had a more acidic isoelectric point. Another isolate (from Africa) initially showed a degree of resistance to inhibition by Papua New Guinea immunoglobulin (although not to the same extent as the Thai parasite), but in later experiments, this isolate was susceptible to inhibition. During the course of this series of experiments, the antigenic composition of this (uncloned) isolate changed so that it became similar (but not identical) to the Papua New Guinea isolates.