Abstract Haemoglobin C (HbC; β6Glu→ Lys) is common in malarious areas of West Africa, especially in Burkina Faso 1, 2. Conclusive evidence exists on the protective role against severe malaria of haemoglobin S (HbS; β6Glu→ Val) heterozygosity 3, whereas conflicting results for the HbC trait have been reported 4, 5, 6, 7, 8, 9, 10 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 11, 12 but HbC homozygotes with high P. falciparum parasitaemias have been observed 10. 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 …