Rationale: High endotoxin exposure may reduce the risk of allergic sensitization. Objective: To determine the relationship between a promoter polymorphism in the CD14 gene (CD14/-159 C to T) and endotoxin exposure in relation to the development of allergic sensitization, eczema, and wheeze within the setting of a birth cohort. Methods: We genotyped 442 children (CD14/-159 C to T; rs2569190). We assessed children for allergic sensitization (IgE > 0.2 kU/L to at least one of seven allergens), eczema (physical examination), and parentally reported wheeze. Endotoxin was measured in house dust. Main Results: Genotype frequencies were consistent with other populations (TT, 25%; CT, 47%; CC, 28%). Sensitization (present in 33% of children) was not associated with genotype. For children with TT and CT genotypes, there was no association between endotoxin and sensitization (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.71-1.23; p = 0.7; and OR, 0.90; 95% CI, 0.77-1.04; p = 0.16, respectively) or endotoxin and eczema (OR, 0.99; 95% CI, 0.81-1.20; p = 0.89; and OR, 1.38; 95% CI, 0.83-2.30; p = 0.22, respectively). In children with the genotype CC, increasing endotoxin load was associated with a marked and significant reduction in the risk of sensitization (OR, 0.70; 95% CI, 0.55-0.89; p = 0.004) and eczema (OR, 0.73; 95% CI, 0.56-0.95; p = 0.02). However, we observed an increased risk of nonatopic wheeze with increasing endotoxin exposure in children with the CC genotype (OR, 1.42; 95% CI, 1.01-1.99; p = 0.04) but not other genotypes. No effect was seen for atopic wheeze. Conclusions: Increasing endotoxin exposure is associated with reduced risk of allergic sensitization and eczema but with increased risk of nonatopic wheeze in children with the CC genotype at -159 of the CD14 gene. The impact of environmental endotoxin may be enhanced in individuals with this genotype.