Previous segregation analysis of a sample of 234 randomly selected Australian families showed evidence for a recessive major gene controlling serum immunoglobulin E (IgE) levels independently of the specific response to allergens (SRA). Since linkage has been recently reported between serum IgE levels and the 5q candidate region spanning the interleukin-4 (IL-4) gene, we investigated whether the recessive major gene detected by segregation analysis was linked to the IL-4 region and whether polymorphisms within the IL-4 gene were associated with IgE levels. Both sib-pair method and combined segregation and linkage analysis using the regressive models were applied to our data. Whereas there was no evidence of linkage of total IgE levels to the IL-4 region, an indication of linkage (P values ranging between 0.01 and 0.03) was found between IgE levels adjusted for SRA and two IL-4 polymorphisms: one dinucleotide repeat in intron 2 of the IL-4 gene and a single nucleotide (-590 C to T) polymorphism in the IL-4 promoter. However, the putative IL-4 linked gene did not appear to be in linkage disequilibrium with either of these two polymorphisms. A contribution of the IL-4 promoter polymorphism, presumed to be a potential functional variant influencing IgE variation, was also excluded.