Apolipoprotein E is a monomeric protein secreted by the liver and responsible for the transport of plasma cholesterol and triglycerides. The APOE gene encodes 3 isoforms E4, E3 and E2 with APOE E4 associated with higher plasma cholesterol levels and increased pathogenesis in several infectious diseases (HIV, HSV). Given that cholesterol is an important nutrient for malaria parasites, we examined whether APOE E4 was a risk factor for Plasmodium infection, in terms of prevalence or parasite density. A cross sectional survey was performed in 508 children aged 1 to 12 years in Gabon during the wet season. Children were screened for Plasmodium spp. infection, APOE and hemoglobin S (HbS) polymorphisms. Median parasite densities were significantly higher in APOE E4 children for Plasmodium spp. densities compared to non-APOE E4 children. When stratified for HbS polymorphisms, median Plasmodium spp. densities were significantly higher in HbAA children if they had an APOE E4 allele compared to those without an APOE E4 allele. When considering non-APOE E4 children, there was no quantitative reduction of Plasmodium spp. parasite densities for HbAS compared to HbAA phenotypes. No influence of APOE E4 on successful Plasmodium liver cell invasion was detected by multiplicity of infection. These results show that the APOE E4 allele is associated with higher median malaria parasite densities in children likely due to the importance of cholesterol availability to parasite growth and replication. Results suggest an epistatic interaction between APOE and HbS genes such that sickle cell trait only had an effect on parasite density in APOE E4 children. This suggests a linked pathway of regulation of parasite density involving expression of these genes. These findings have significance for understanding host determinants of regulation of malaria parasite density, the design of clinical trials as well as studies of co-infection with Plasmodium and other pathogens.