INTRODUCTION: Vitamin D deficiency has been associated with many chronic illnesses, but little is known about its relation with chronic obstructive pulmonary disease (COPD). OBJECTIVES: We measured serum 25-hydroxyvitamin D levels (25-OHD) in 414 (ex)-smokers older than 50 years and assessed the link between vitamin D status and presence of COPD. The rs7041 and rs4588 variants in the vitamin D binding gene (GC) were genotyped and their effects on 25-OHD levels were tested. RESULTS: In COPD patients 25-OHD levels correlated significantly with FEV1 (r = 0.28, p<0.0001). Compared to 31% of the smokers with normal lung function, as much as 60% and 77% of GOLD stage 3 and 4 patients exhibited deficient 25-OHD levels lower than 20ng/ml (p<0.0001). Additionally, 25-OHD levels were reduced by 25% in homozygous carriers of the rs7041 at-risk T-allele (p<0.0001). This correlation was found to be independent of COPD severity, smoking history, age, gender, body mass index, corticosteroid intake, seasonal variation and rs4588 (p<0.0001). Notably, 76% and 100% of GOLD stage 3 and 4 patients homozygous for the rs7041 T-allele, exhibited 25-OHD levels lower than 20ng/ml. Logistic regression corrected for age, gender and smoking history, further revealed that homozygous carriers of the rs7041 T-allele exhibited an increased risk for COPD (OR=2.11; 95% CI: 1.20-3.71; p=0.009). CONCLUSION: Vitamin D deficiency occurs frequently in COPD and correlates with severity of COPD. Our data warrant vitamin D supplementation in patients with severe COPD, especially in those carrying at-risk rs7041 variants.