Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with significant and increasing morbidity and mortality. The cardinal feature of COPD is persistent airflow obstruction, measured by reductions in quantitative spirometric indices including forced expiratory volume at one second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC). However, many patients have substantial improvement in spirometric measures with inhaled bronchodilator medications, and bronchodilator responsiveness (BDR) has been associated with disease severity and progression. To identify susceptibility loci for BDR phenotypes, we performed a 9 cM genome scan in 72 pedigrees (n = 560 members) ascertained through probands with severe, early-onset COPD. Multipoint variance component linkage analysis was performed for quantitative phenotypes including BDR measures and post-bronchodilator FEV1 and FEV1/FVC. Post-bronchodilator FEV1 was linked to multiple regions, most significantly to markers on chromosome 8p (LOD = 3.30) and 1q (LOD = 2.24). Post-bronchodilator FEV1/FVC was also linked to multiple regions, most significantly to markers on chromosome 2q (LOD = 4.42) and 1q (LOD = 2.52). When compared with pre-bronchodilator spirometric indices, the post-bronchodilator values demonstrated increased evidence of linkage in multiple genomic regions. In particular, the LOD score for the 8p linkage to FEV1 roughly doubled from 1.58 to 3.30. Candidate regions on chromosomes 4p (LOD = 1.28), 4q (LOD = 1.56), and 3q (LOD = 1.50) gave the strongest evidence for linkage to BDR measures. Our results provide evidence for significant linkage to airflow obstruction susceptibility loci on chromosomes 2q and 8p, and further suggest that post-bronchodilator spirometric measures are optimal phenotypes for COPD genetic studies. This study has also identified several genomic regions that could contain loci regulating BDR in early-onset COPD families.