ABSTRACTHuman mannose-binding lectin (MBL) encoded by the MBL2gene is a pattern recognition protein and has been associated with many infectious diseases, including malaria. We sought to investigate the contribution of functional MBL2gene variations to Plasmodium falciparummalaria in well-defined cases and in matched controls. We resequenced the 8.7 kb of the entire MBL2gene in 434 individuals clinically classified with malaria from regions of India where malaria is endemic. The study cohort included 176 patients with severe malaria, 101 patients with mild malaria, and 157 ethnically matched asymptomatic individuals. In addition, 830 individuals from 32 socially, linguistically, and geographically diverse endogamous populations of India were investigated for the distribution of functional MBL2variants. The MBL2 -221C(X) allelic variant is associated with increased risk of malaria (mild malaria odds ratio [OR] = 1.9, corrected Pvalue [PCorr] = 0.0036; severe malaria OR = 1.6, PCorr= 0.02). The exon1 variants MBL2*B(severe malaria OR = 2.1, PCorr= 0.036; mild versus severe malaria OR = 2.5, PCorr= 0.039) and MBL2*C(mild versus severe malaria OR = 5.4, PCorr= 0.045) increased the odds of having malaria. The exon1 MBL2*D/*B/*Cvariant increased the risk for severe malaria (OR = 3.4, PCorr= 0.000045). The frequencies of low MBL haplotypes were significantly higher in severe malaria (14.2%) compared to mild malaria (7.9%) and asymptomatic (3.8%). The MBL2*LYPAhaplotypes confer protection, whereas MBL2*LXPAincreases the malaria risk. Our findings in Indian populations demonstrate that MBL2functional variants are strongly associated with malaria and infection severity.