BackgroundMalaria is a deadly disease caused byPlasmodiumspp. Several blood phenotypes have been associated with malarial resistance, which suggests a genetic component to immune protection.MethodsOne hundred and eighty-seven single nucleotide polymorphisms (SNPs) in 37 candidate genes were genotyped and investigated for associations with clinical malaria in a longitudinal cohort of 349 infants from Manhiça, Mozambique, in a randomized controlled clinical trial (RCT) (AgeMal, NCT00231452). Malaria candidate genes were selected according to involvement in known malarial haemoglobinopathies, immune, and pathogenesis pathways.ResultsStatistically significant evidence was found for the association ofTLR4and related genes with the incidence of clinical malaria (p = 0.0005). These additional genes includeABO,CAT,CD14,CD36,CR1,G6PD,GCLM,HP,IFNG,IFNGR1,IL13,IL1A,IL1B,IL4R,IL4,IL6,IL13,MBL,MNSOD, andTLR2. Of specific interest, the previously identifiedTLR4SNP rs4986790 and the novel finding of TRL4 SNP rs5030719 were associated with primary cases of clinical malaria.ConclusionsThese findings highlight a potential central role of TLR4 in clinical malarial pathogenesis. This supports the current literature and suggests that further research into the role ofTLR4, as well as associated genes, in clinical malaria may provide insight into treatment and drug development.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12936-023-04549-8.