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Using segregation analyses, control of malaria parasites has previously been linked to a major gene within the chromosomal region 5q31–33, but also to complex genetic factors in which effects are under substantial age-dependent influence. However, the responsible gene variants have not yet been identified for this chromosomal region. In order to perform association analyses of 5q31–33 locus candidate single nucleotide polymorphisms (SNPs), 1015 children were recruited at the age of 3 months and followed monthly until the age of 2 years in an area holoendemic for Plasmodium falciparum malaria in Ghana. Quantitative (incidence rates of malaria episodes) and qualitative phenotypes (i.e. ‘more than one malaria episode’ or ‘not more than one malaria episode’) were used in population- and family-based analyses. The strongest signal was observed for the interleukin 3 gene (IL3) SNP rs40401 (P = 3.4 × 10−7, Pc= 1.4 × 10−4). The IL3 genotypes rs40401CT and rs40401TT were found to exert a protective effect of 25% [incidence rate ratio (IRR) 0.75, P = 4.1 × 10−5] and 33% (IRR 0.67, P = 3.2 × 10−8), respectively, against malaria attacks. The association was confirmed in transmission disequilibrium tests (TDT, qTDT). The results could argue for a role of IL3 in the pathophysiology of falciparum malaria.