Bronchial hyperresponsiveness (BHR) is a hallmark of asthma and represents a strong risk factor for the disease. However, not all asthmatics have BHR and it can be observed in normal subjects too, probably because of genetic predisposition. Increasing attention is being focused on the beta2-adrenoceptor gene (ADRB2), whose genetic variability at amino acids 16 and 27 has been shown to correlate with some clinical features of asthma, including airways reactivity. To verify whether ADRB2 gene polymorphisms can influence BHR at a broader level, we studied a large, highly homogeneous sample of individuals sharing race, gender, age, and current living environment. BHR was strictly defined as a constant positive response to serial methacholine challenge tests and an improved definition of genetic variability at the ADRB2 locus was used, by identifying the haplotypic combinations of polymorphisms 16 and 27. We observed that the ADRB2 haplotype with a Gly at position 16 and a Gln at position 27 is associated with BHR in our sample. The association persisted also after correction for potentially confounding variables such as specific and total IgE levels. This observation suggests therefore that ADRB2 gene can confer genetic susceptibility to BHR, rather than having only a disease-modifying effect in asthma.