Genetic predisposition to malaria has been shown by epidemiological, case-control and linkage studies. In particular, case-control studies have recently shown association between hemoglobin C and resistance to severe malaria in Mali and to clinical malaria in Burkina Faso. In a longitudinal study of families living in an endemic area, we investigated whether hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack. We surveyed 256 individuals (71 parents and 185 sibs) from 53 families during 2 years. Hemoglobin C carriers had less frequent malaria attacks than AA individuals within the same age group (P=0.01). Since age correlated with malaria attack and parasitemia (P<0.0001), we took age into account in association analyses. We performed combined linkage and association analyses, which avoid biases due to population structure. Using multi-allelic tests, we evidenced association between hemoglobin genotype and phenotypes related to malarial infection and disease (P<0.001). We further analyzed individual hemoglobin alleles and detected negative association between hemoglobin C and malaria attack (P=0.00013). Analyses that took into account confounding factors confirmed the negative association of hemoglobin C with malaria attack (P=0.0074) and evidenced a negative correlation between hemoglobin C and parasitemia (P=0.0009). These associations indicate that hemoglobin C reduces parasitemia and confers protection against mild malaria attack.