Introduction: There are limited data linking serum levels of surfactant protein D, its genetic polymorphisms to the risk of Chronic Obstructive Pulmonary Disease (COPD). Objectives: We sought to investigate these relationships using a case control study design.Methods: Post bronchodilator values of FEV1/FVC <0.7 were used to diagnose COPD patients (n = 115). Controls were healthy subjects with normal spirometry (n = 106) Single nucleotide polymorphisms (rs721917, rs2243639, rs3088308) were genotyped using polymerase chain reaction (PCR) and restriction analysis. Serum SP-D levels were measured using a specific immunoassay.Results: Allele ‘A’ at rs3088308 (p < 0.00, B = −0.41) and ‘C’ allele at rs721917 (p = 0.03; B = −0.30) were associated with reduced serum SP-D levels. Genotype ‘T/T’ at rs721917 was significantly associated with risk of COPD (p = 0.01). Patients with repeat exacerbations had significantly higher serum SP-D even after adjusting for genetic factors.Conclusions: We report for the first time that rs3088308 is an important factor influencing systemic SP-D levels and confirm the previous association of rs721917 to the risk of COPD and serum SP-D levels.