Background: Macrophages play an important role in COPD. We genotyped at-risk smokers to evaluate the role of polymorphisms in the macrophage scavenger receptor-1 gene (MSR1) in COPD susceptibility and related measures of lung function. Then, in macrophages from donors with specific MSR1 genotypes, we determined the effect of MSR1 single nucleotide polymorphisms (SNPs) on macrophage function by examining in vitro adhesion, receptor expression, and cell number in culture as an index of increased survival/reduced apoptosis. Methods: Smokers (≥ 20 pack-years) who were > 40 years(n = 714) were genotyped for seven SNPs; one nonsense change (ex6R293x-C/T), four missense changes (ex4V113A-T/C, ex4P174Y-G/T, ex11H441R-A/G, and in the ligand binding site ex6P275A-C/G), -176511-A/G in the promoter region, and IVS5-59-C/A in the intron. Nonsmoking healthy volunteers (n = 85) were genotyped, and peripheral blood monocytes were isolated from seven P275A-CG/GG and eight P275A-CC controls and cultured to generate monocyte-derived macrophages (MDM). The effectiveness of trypsin and scraping to dislodge MDM was scored on a four-point subjective scale. MDM were counted on a Z1 particle counter and surface expression of MSR1 was determined by fluorescence-activated cell sorting analysis using secondary staining of antibodies against human macrophage scavenger receptor (MSR1). Results: The MSR1-coding SNP P275A was associated with susceptibility to COPD in smoklt;.005) and a lower percent predicted (pp) FEV1, FEV 1/FVC, and pp forced expiratory flow (FEF)25-75 (P =.03). P275A-CG/GG was also associated with increases in maintenance of cell number in culture (increased survival/reduced apoptosis), MSR1 expression, and adhesion of macrophages to plastic in vilt;.05). Conclusions: The MSR1 association with COPD susceptibility, COPD-related measures of lung function, and abnormalities of macrophage function may account for significant COPD morbidity.