Abstract Background Antigen-specific antibody-mediated immune responses play an important role in natural protection against clinical malaria, but conflicting estimates of this association have emerged from immuno-epidemiological studies in different geographical settings. This study was aimed at assessing in a standardized manner the relationship between the antibody responses to four malaria vaccine candidate antigens and protection from clinical malaria, in a cohort of Ghanaian children. Methods Standardized ELISA protocols were used to measure isotype and IgG subclass levels to Apical Membrane Antigen 1 (AMA1), Merozoite Surface Protein 1–19 (MSP1 19 ), Merozoite Surface Protein 3 (MSP3) and Glutamate Rich Protein (GLURP) antigens in plasma samples from 352 Ghanaian children, aged three to 10 years with subsequent malaria surveillance for nine months. This is one of a series of studies in different epidemiological settings using the same standardized ELISA protocols to permit comparisons of results from different laboratories. Results The incidence rate of malaria was 0.35 episodes per child per year. Isotype and IgG subclasses for all antigens investigated increased with age, while the risk of malaria decreased with age. After adjusting for age, higher levels of IgG to GLURP, MSP1 19 , MSP3 and IgM to MSP1 19 , MSP3 and AMA1 were associated with decreased malaria incidence. Of the IgG subclasses, only IgG1 to MSP1 19 was associated with reduced incidence of clinical malaria. A previous study in the same location failed to find an association of antibodies to MSP1 19 with clinical malaria. The disagreement may be due to differences in reagents, ELISA and analytical procedures used in the two studies. When IgG, IgM and IgG subclass levels for all four antigens were included in a combined model, only IgG1 [(0.80 (0.67–0.97), p = 0.018)] and IgM [(0.48 (0.32–0.72), p