Significant differences in immune responses upon vaccination have been described, suggesting genetics are important in determining the magnitude of vaccine responses. The interleukin (IL)-4 pathway, including IL-4, IL-13 and the IL-4 receptor alpha chain (IL-4 Ralpha), is central to humoral responses and therefore could have an impact on vaccine responsiveness.To investigate whether single nucleotide polymorphisms (SNPs) in the IL-4, IL-13 and IL-4 RA genes influence pneumococcal serotype-specific IgG antibody responses.SNPs in the IL-4 gene (C -589T, G2979T), the IL-13 gene (G -1112A, Arg130Gln) and in the IL-4 RA gene (Ile50Val, Gln551Arg) were investigated in isolation and in combination, for their influence on serotype-specific IgG antibody responses upon combined pneumococcal conjugate and polysaccharide vaccinations in children with a history of recurrent otitis media.Lower antibody responses were observed for alleles previously associated with atopy, IL-4 -589T, IL-4 2979T and IL-4 Ralpha 551Gln. Effects were stronger in gene haplotype combinations or in multiple haplotype combination analyses.This study highlights the importance of host genetic factors in vaccine responses. Furthermore, it supports the approach of studying the effect of combinations of multiple alleles, in haplotypes or in combinations of haplotypes, on complex phenotypes within a biological pathway.