Background: Several studies have indicated linkage of chromosome 11q12-13 to asthma and associated traits. Among other candidate genes, the Clara cell protein 16 (CC16) gene maps to this region. CC16 is expressed in the bronchial epithelium and exhibits potent anti-inflammatory properties. A single-nucleotide polymorphism (SNP) in the CC16 gene (A38G) was previously associated with asthma. Objective: We evaluated the role of the CC16 SNP in pediatric asthma and asthma severity in 2 German study populations. Methods: The German Multicenter Allergy Study (MAS) cohort (n = 872, 94 asthmatic patients) and 112 allergic asthmatic children recruited in Freiburg, Germany, were included in the pres-ent study. Histamine provocations were performed at the age of 7 years in the MAS cohort to determine bronchial hyperreactivity; in the Freiburg study population a standardized exercise-induced decrease in FEV₁ was evaluated. For genotyping, melting-curve analysis and restriction enzyme digestion were applied. Results: No association of the CC16*38A allele with asthma could be observed in either study population. However, in asthmatic subjects (MAS cohort) PC₂₀FEV₁ values were significantly lower in individuals homozygous or heterozygous for the CC16*38A allele compared with those in subjects with the CC16*38GG genotype (P < .05 and P < .03, respectively). Similarly, allergic asthmatic patients in the Freiburg cohort showed a significantly greater decrease in FEV₁ after exercise when homozygous for the CC16*38A allele compared with that seen in asthmatic patients with the *38AG or *38GG genotype (P < .04 and P = .006, respectively). Conclusion: We conclude that the CC16*A38G SNP influences bronchial hyperreactivity and might be a genetic determinant of asthma severity in German children. (J Allergy Clin Immunol 2003;111:515-9.)