The gene for Clara cell 16-kDa (CC16) protein is a promising candidate for asthma susceptibility. The CC16 38A allele has been associated with decreased CC16 plasma levels and increased incidence of asthma in Australian children. To date these results have not been replicated in adults. Therefore, potential links between CC16 A38G, asthma and atopy were investigated in an unselected population of young adult Danes. Four hundred sixty-four Danes, aged 19-29 years, from Copenhagen participated in an asthma and allergy phenotype - genotype study. Genotyping was done by Sau96I restriction digestion of PCR products spanning the A38G polymorphism. Potential A38G genotype and asthma-related phenotype associations were investigated using regression analysis, adjusting for potential confounders where appropriate. Adults with the 38AA genotype had higher odds of current asthma ( OR 3.2, P=0.013) and ever asthma ( OR 2.2, P= 0.045) compared with those with the 38GG genotype. Adjusting for atopy had minimal effect on this relationship. A positive linear trend was evident between the 38A allele and atopic dermatitis ( OR 1.67, P= 0.02). No associations were found between the A38G polymorphism and rhinitis, atopy, forced expiratory volume in 1 s ( FEV1), forced vital capacity ( FVC), airway responsiveness (AR) to histamine or peripheral blood eosinophil level (PBEL). An atopy-independent association between CC16 38AA and asthma prevalence was identified, suggesting the CC16 38A allele predisposes to adult asthma independent of Th1/Th2 processes. This finding is consistent with previous studies in children, but is the first reported association between CC16 A38G and asthma in adults. CC16 38A also displayed a positive linear trend with atopic dermatitis.