Both spontaneous and treatment-induced clearance of hepatitis C virus (HCV) in adults have been associated with genetic polymorphisms in the interferon-λ genes. The aim of the present study was to confirm the association between the rs12979860 and evaluate the association between the rs368234815 and the rs4803217 single-nucleotide polymorphisms (SNPs) of the interferon-λ genes and the outcome of the infection in children.Alleles and genotypes frequencies of 32 children, who presented spontaneous clearance of the virus and 135 children, with viral persistence were compared with ethnically matched controls obtained from the 1000 Genomes Project and the International HapMap Project databases.The frequencies of the C/C genotype of rs12979860, the TT/TT of the rs368234815 and the A/C of the rs4803217 were higher in the clearance group than in children with viral persistence (C/C versus T/T + C/T odds ratio (OR): 2.6; 90% confidence intervals (CI): 1.3-5; p = 0.01; TT/TT versus ΔG/TT + ΔG/ΔG OR: 2.8; 90% CI: 1.4-5.5; p = 0.01; and A/A versus A/C OR: 8.3; 90% CI: 1.5-45.9; p = 0.017, respectively) and with the ethnically matched controls.The rs12979860, the rs368234815 and the rs4803217 SNPs are associated with spontaneous clearance of HCV in children.Innate immune system response has a key role in the outcome of vertically acquired HCV infection in children. The rs12979860, the rs368234815 and the rs4803217 SNPs are associated with spontaneous clearance of HCV in children. Interferons-λ activate the Janus kinase-Stat pathway, which in turn induces several interferon-stimulated genes, leading to suppression of HCV replication both in vivo and in vitro.