Sex differences in asthma-associated phenotypes are well known but the genetic factors that may account for these differences have received little attention. This study aimed to characterize sex-specific and pleiotropic genetic factors underlying four quantitative phenotypes involved in the main asthma physiopathological pathways: immunoglobulin E levels, a measure of polysensitization (SPTQ), eosinophil counts and a measure of lung function FEV(1)/H(2) (forced expiratory volume in one second divided by height square). Sex-stratified univariate and bivariate linkage analyses were conducted in 295 families from the Epidemiological study on the Genetics and Environment of Asthma study. We found genome-wide significant evidence for a male-specific pleiotropic QTL (quantitative trait loci) on 5q31 (P=7 x 10(-9)) influencing both FEV(1)/H(2) and SPTQ and for a female-specific pleiotropic QTL on 11q23 underlying SPTQ and immunoglobulin E (P=2 x 10(-5)). Three other sex-specific regions of linkage were detected for eosinophil: 4q24 and 22q13 in females, and 3p25 in males. Further, bivariate association analysis of FEV(1)/H(2) and SPTQ with 5q31 candidate genes in males showed a significant association with two single-nucleotide polymorphisms within IL9 gene, rs2069885 and rs2069882 (P=0.02 and P=0.002, respectively, after Bonferroni's correction). This study underlies the importance of taking into account complex mechanisms, such as heterogeneity according to sex and pleiotropy to unravel the genes involved in asthma phenotypes.