Cumulative evidence indicates that the human interleukin-4 receptor alpha chain gene (IL-4Ralpha, CD124) is highly polymorphic in contrast to other cytokine receptor genes. Our group recently identified the IL-4Ralpha variant R551 as being strongly associated with decreased kidney allograft survival. Due to the key immunoregulatory role of IL-4 and controversial reports on the association of IL-4Ralpha variants with atopy, we present here the development of polymerase chain reaction-primer sets for sequence-specific amplification of all seven hitherto described amino acid polymorphisms, and we investigated 158 blood donors prospectively. By using an Expectation-Maximization algorithm, we calculated the presence of 11 putative human IL-4Ralpha haplotypes and identified 4 putative IL-4Ralpha haplotypes with a cumulative frequency of >90%. None of the polymorphisms showed a significant association with the phenotype atopy. All mutant alleles showed a trend toward decreased total IgE levels. This association was only significant (p < 0.05; Mann-Whitney U-test) for the A375, R406, and P478 variants in non-atopic blood-donors (n = 90), presumably due to the high variance of IgE levels among the smaller group of atopic individuals. We postulate that IL-4Ralpha mutations are associated to different extents with a decrease in function of the receptor but do not present a major atopy locus.