Background: Early exposure to microbial matter such as LPS may influence the development of asthma and allergies by activation of innate immunity pathways as indicated by studies in farming environments. Recently, polymorphisms in caspase recruitment domain containing protein 15 (CARD15), an intracellular LPS receptor protein, have been associated with Crohn's disease. Because these polymorphisms lead to changes in LPS recognition, they may affect the development of asthma and allergies. Objective: We genotyped a large population of German schoolchildren (N = 1872) from East and West Germany for 3 functional relevant CARD15 polymorphisms for their role in the development of asthma and allergy. Methods: By use of parental questionnaires, skin prick testing, pulmonary function tests, bronchial challenge tests, and measurements of serum IgE levels, children were phenotyped for the presence of atopic diseases. Genotyping was performed with PCR-based restriction enzyme assays. To assess associations between atopic phenotypes and genotypes standard statistical procedures were applied. Results: Children with the polymorphic allele C2722 had a more than 3-fold risk to develop allergic rhinitis (P < .001) and an almost 2-fold risk for atopic dermatitis (P < .05). Furthermore, the T2104 allele was associated with an almost 2-fold risk for allergic rhinitis (P < .05). When a C insertion at position 3020 was present, the risk of atopy increased by 50% (P < .05) and serum IgE levels were elevated (P < .01). Conclusion: The shared genetic background between Crohn's disease and atopy may indicate that an impaired recognition of microbial exposures results in an insufficient downregulation of excessive immune responses, giving rise to either T_H2 dominated allergies or T_H1 related Crohn's disease. (J Allergy Clin Immunol 2003;111:813-7.)