Asthma is a complex disease and the intricate interplay between genetic and environmental factors underlies the overall phenotype of the disease. Families with at least two siblings with asthma were collected from Europe, Australia and the US. A genome scan using a set of 364 families with a panel of 396 microsatellite markers was conducted. Nonparametric linkage analyses were conducted for asthma and three asthma-related phenotypes: bronchial hyper-reactivity (BHR), strict definition of asthma and atopic asthma. Nine chromosomal regions with LOD scores greater than 1.5 were identified ( chromosomes 1q, 2p, 3q, 4p, 4q, 6q, 12q, 20p and 21). Linkage refinement analysis was performed for three BHR loci by genotyping single nucleotide polymorphisms at an average marker density of 1 cM. The LOD scores increased to 3.07 at chromosome 4p and 4.58 at chromosome 2p, while the chromosome 6p locus did not refine. The LOD score at the chromosome 2p locus is highly significant on a genome-wide basis. The refined locus covers a region with a physical size of 12.2 Mb. Taken together, these results provide evidence for a major asthma susceptibility locus on chromosome 2p.