Although peripheral blood eosinophilia is strongly associated with the risk of developing asthma, genetic determinants of eosinophilia have not been extensively studied. We used sib-pair analysis to assess linkage of circulating eosinophils (as a percent of total white blood cells [WBC]) to nine markers located in chromosome 5q31-33. The study was divided into two phases. Of 246 sib pairs available for the first phase, 35 were classified as low concordant (LC) (both sibs had <= 2% circulating eosinophils), 18 were defined as high concordant (HC) (both sibs had 5% or more circulating eosinophils), and 26 were defined as discordant (one sib had <= 2% and the other sib had 5% or more circulating eosinophils). Significant evidence for linkage among low concordant sib pairs was found for several markers in the region under study, with a peak for marker D5S500 (proportion of alleles shared identical by descent [ibd] = 0.68 +/- 0.05 [mean +/- SE], p = 0.0004). A cross-validating study was done in which an additional 19 sib pairs that were low concordant for circulating eosinophils were studied. Evidence for linkage was also observed in this subset. Results were independent of current wheezing, total serum IgE levels, and other potential confounders. A multipoint analysis done for all low-concordant sib pairs available showed that the maximal logarithm of the odds favoring genetic linkage (LOD) score (2.4, p = 0.0004) was observed in correspondence with marker D5S658. We conclude that a locus or loci may be present in chromosome 5q31-33 that controls for circulating eosinophils as a proportion of total WBC.