Surfactant protein D (SFTPD) induces emphysema in knockout mice, but the association of SFTPD with chronic obstructive pulmonary disease (COPD) and emphysema in humans is unclear. Therefore, we aimed to determine the association between genetic variations in SFTPD and susceptibility to COPD and emphysema.Two populations were studied: population A comprised 270 smokers, including 188 COPD and 82 at-risk subjects, and population B comprised 1131 autopsy cases including 160 cases with emphysema. Six single-nucleotide polymorphisms (SNPs) that tagged the linkage disequilibrium blocks on the entire SFTPD gene were genotyped; the associations of the genotypes with COPD, pulmonary function, percentage of the low-attenuation area (LAA%), and percentage of the airway wall area (WA%) were determined in population A. In population B, the associations of the genotypes with emphysema were assessed.A C allele at SNP rs721917 that results in the replacement of Met with Thr at position 11 in SFTPD was positively correlated with the LAA% in the upper lung (P = 1.1 × 10(-5)) and overall LAA% (P = 1.0 × 10(-4)), and negatively correlated with the serum concentration of SFTPD (P = 7 × 10(-11)) in the population A. The C/C (rs721917/rs10887199) haplotype was associated with emphysema in both the populations.Subjects with a C allele at rs721917 have a lower serum SFTPD concentration and are more susceptible to emphysema. This suggests a protective effect of SFTPD against COPD and emphysema.