The contribution of mannose-binding lectin (MBL) to protection from malaria was assessed by comparing plasma concentrations of MBL and the frequency of MBL gene polymorphisms in groups of Gabonese children participating in a prospective study of severe and mild malaria due to infection with Plasmodium falciparum. At admission, a higher proportion of patients with severe malaria had a low level of MBL compared with subjects with mild malaria (0.35 vs. 0.19, P = .02). Two mutations in codons 54 and 57 of the MBL gene were detected. They were present at higher frequency in those with severe malaria (0.45 vs. 0.31, P = .04). These results suggest that deficient innate immune responses, in the form of low MBL levels, may be a risk factor for severe malaria in some young children who lack well-developed, clinically protective acquired immune responses.