Haemoglobin C (HbC; β6Glu → Lys) is common in malarious areas of West Africa, especially in Burkina Faso^,. Conclusive evidence exists on the protective role against severe malaria of haemoglobin S (HbS; β6Glu → Val) heterozygosity, whereas conflicting results for the HbC trait have been reported^,,,,,, and no epidemiological data exist on the possible role of the HbCC genotype. In vitro studies suggested that HbCC erythrocytes fail to support the growth of P. falciparum^, but HbC homozygotes with high P. falciparum parasitaemias have been observed. Here we show, in a large case–control study performed in Burkina Faso on 4,348 Mossi subjects, that HbC is associated with a 29% reduction in risk of clinical malaria in HbAC heterozygotes (P = 0.0008) and of 93% in HbCC homozygotes (P = 0.0011). These findings, together with the limited pathology of HbAC and HbCC compared to the severely disadvantaged HbSS and HbSC genotypes and the low β^S gene frequency in the geographic epicentre of β^C,,, support the hypothesis that, in the long term and in the absence of malaria control, HbC would replace HbS in central West Africa.