Background: Multiple genetic factors are associated with the risk of developing COPD. One of the leading candidates is the gene encoding vitamin D binding protein (VDBP). We sought to investigate the types of VDBP variants in the Korean population and determine the association of VDBP variants with COPD and airflow deterioration. Methods: The study cohort consisted of 203 COPD patients and 157 control subjects. VDBP variants were genotyped by the RFLP method. All lung function data were analyzed using a linear mixed model. Results: GC1F variant was most frequently observed both in COPD (42.8%) and controls (38.6%). Genotype 1S-1S was more commonly detected in controls than in COPD (8.4% versus 3.4%, P=0.047). According to linear mixed model analysis, subjects with genotype 1S-1S had 0.427 L higher FEV1 than those with other genotypes (P=0.029). However, the genotype/smoking pack-year interaction was found to be particularly significant among subjects with genotype 1S-1S; FEV1 decreased by 0.014L per smoking pack-year (P=0.001). Conclusions: VDBP genotype 1S-1S was significantly associated with lung function decline in patients who smoke. Lung function decline in subjects with genotype 1S-1S was more prominent as the amount of pack-years increased compared to subjects with other genotypes (a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare (A102065), a grant of the Korea Centers for Disease Control and Prevention (2006-E71011-00), and a Faculty Research Grant of Yonsei University College of Medicine for 2011 (6-2011-0192)).