Antibodies to the C terminus of the Plasmodium falciparum merozoite surface protein, PfMSP-1(19), may inhibit merozoite invasion or block the effects of inhibitory antibodies. Here, using a competition enzyme-linked immunosorbent assay and antibody binding to wild-type and mutated recombinant proteins, we show that there are marked variations between individuals in the fine specificity of naturally acquired anti-MSP-1(19) antibodies. Furthermore, although neither the prevalence nor the concentration of total anti-MSP-1(19) antibodies was associated with resistance to malaria in African children, significant associations were observed between antibody fine specificity and subsequent risk of infection and high-density parasitemia during a follow-up period. Thus, the fine specificity of naturally acquired human anti-MSP-1(19) antibodies is crucial in determining their function. Future field studies, including the evaluation of PfMSP-1 vaccine trials, should include assays that explore antibody fine specificity as well as titer.