Background: Eotaxin, a CC chemokine expressed in the asthmatic lung, has been associated with impaired lung function. The role of its variant form is unknown. Objective: The purpose of this study was to detect the population frequency and effects of a known single-nucleotide polymorphism in the eotaxin gene in which a threonine residue (THR₂₃) is substituted for the wild-type alanine (ALA₂₃) at the 23rd amino acid at the terminus of the peptide leader sequence. Methods: We measured eotaxin protein secretion in 293 cells transfected with expression vectors and in PBMCs obtained from individuals bearing the alternative forms of the gene. A case-control study of plasma eotaxin levels and eosinophil counts, a comparison of baseline lung function by genotype in a population of 806 subjects with asthma, and a comparison of the allele frequency with a nonasthmatic population were performed. Results: Human 293 cells and PBMCs with THR₂₃ variant eotaxin secreted significantly less eotaxin protein than did ALA₂₃-bearing cells. In the case-control study, THR₂₃-THR₂₃ individuals had lower plasma levels of eotaxin (310 [240-350] vs 420 [270-700] pg/mL; P < .05) and eosinophil counts (120 [5-220] vs 190 [110-470] cells/μL; P < .05) than ALA₂₃-ALA₂₃ subjects; heterozygous subjects had intermediate levels. Higher levels of lung function were associated with THR₂₃ eotaxin (percent of predicted FEV₁, 65% ± 3.5% [THR₂₃-THR₂₃] vs 58% ± 0.9% [THR₂₃-ALA₂₃] and 56% ± 0.5% [ALA₂₃-ALA₂₃]; P < .05). Conclusion: The THR₂₃ variant is associated with both decreased eosinophil counts and higher levels of lung function in subjects with asthma. (J Allergy Clin Immunol 2001;108:946-53.)