The objective of this study was to determine the prevalence of antibodies recognizing the circumsporozoite (CS) protein of Plasmodium by an enzyme-linked immunosorbent assay, in 2 subpopulations of women with significantly different enlarged spleen rates but similar exposure to malaria, on the north coast of Papua New Guinea. Antibody levels of immunoglobulin G (IgG) antibody to CS protein in the high and low spleen rate groups were similar (56.2% and 55.1%) but there was a significant difference in IgM (29.6% and 16.7%). In neither group did antibodies increase with parity (age). In both groups a high level of either IgG or IgM antibody to CS protein was associated with a high spleen rate and women with hyper-reactive malarious splenomegaly were more likely to be positive for both. Lower parasite rates were associated only with increased IgM antibody titres. High levels of antibody to blood-stage parasites were also present in the high spleen rate group, suggesting that antibodies to the CS protein were not protective. It is considered that cell-mediated immunity may be deficient in women with persistent splenomegaly.