Total serum immunoglobulin (Ig)E levels are genetically regulated, but the mechanism of inheritance is not well understood. Cytokines produced by T-helper (Th)1 and Th2 lymphocytes control IgE synthesis. Bacterial antigens may favor the development of Th1 cells from naive CD4-positive T cells through a CD14-dependent pathway. CD14 is constitutively expressed on the surface of monocytes and macrophages, and is also present in serum in a soluble form (sCD14). The CD14 gene maps to chromosome 5q31.1, a candidate region for loci regulating total serum IgE. We hypothesized that genetic variants in the CD14 gene could influence Th-cell differentiation and thus total serum IgE. We identified a C-to-T transition at base pair −159 from the major transcription start site (CD14/−159). Among 481 children recruited from a general population sample, frequency of allele C was 51.4%. TT homozygotes had significantly higher sCD14 levels than did carriers of both the CC and CT genotypes (P = 0.01). TT homozygotes also had significantly lower levels of IgE than did carriers of the other two genotypes, but differences were significant only among children who were skin test–positive to local aeroallergens (P = 0.004). There was no association between CD14/−159 and either interleukin (IL)-4 or interferon (IFN)-γ responses by peripheral blood mononuclear cells. However, IFN-γ and IL-4 responses were positively and negatively correlated, respectively, with serum sCD14 levels. We conclude that CD14/−159 plays a significant role in regulating serum sCD14 levels and total serum IgE levels.