Eliminating schistosomiasis as a public health problem by 2030 requires a better understanding of the disease transmission, especially the asymmetric distribution of worm burden in individuals living and sharing the same environment. It is in this light that this study was designed to identify human genetic determinants associated with high burden ofS. mansoniand also with the plasma concentrations of IgE and four cytokines in children from two schistosomiasis endemic areas of Cameroon. In school-aged children of schistosomiasis endemic areas of Makenene and Nom-Kandi of Cameroon,S. mansoniinfections and their infection intensities were evaluated in urine and stool samples using respectively the Point-of-care Circulating Cathodic Antigen test (POC-CCA) and the Kato Katz (KK) test. Thereafter, blood samples were collected in children harbouring high burden of schistosome infections as well as in their parents and siblings. DNA extracts and plasma were obtained from blood. Polymorphisms at 14 loci of five genes were assessed using PCR-restriction fragment length polymorphism and amplification-refractory mutation system. The ELISA test enabled to determine the plasma concentrations of IgE, IL-13, IL-10, IL-4 and IFN-γ. The prevalence ofS. mansoniinfections was significantly higher (P < 0.0001for POC-CCA;P = 0.001for KK)in Makenene (48.6% for POC-CCA and 7.9% for KK) compared to Nom-Kandi (31% for POC-CCA and 4.3% for KK). The infection intensities were also higher (P < 0.0001for POC-CCA;P = 0.001for KK)in children from Makenene than those from Nom-Kandi. The allele C of SNP rs3024974 ofSTAT6was associated with an increased risk of bearing high burden ofS. mansoniboth in the additive (p= 0.009) and recessive model (p= 0.01) while the allele C of SNP rs1800871 ofIL10was protective (p= 0.0009) against high burden ofS. mansoni. The alleles A of SNP rs2069739 ofIL13and G of SNP rs2243283 ofIL4were associated with an increased risk of having low plasma concentrations of IL-13 (P=0.04) and IL-10 (P=0.04), respectively. This study showed that host genetic polymorphisms may influence the outcome (high or low worm burden) ofS. mansoniinfections and also the plasma concentrations of some cytokines.