OBJECTIVE The scavenger receptor A-I/II (SRA-I/II) on alveolar macrophages is involved in recognition and clearance of modified lipids and inhaled particulates. A rare variant of the SRA-I/II gene, Arg293X, truncates the distal collagen-like domain, which is essential for ligand recognition. We tested whether the Arg293X variant is associated with reduced lung function and risk of chronic obstructive pulmonary disease (COPD) in the general population. METHODS We genotyped 48,741 individuals from the adult Danish general population for Arg293X, and recorded lung function and spirometry-defined COPD. RESULTS Arg293X homozygotes (n = 5) and heterozygotes (n = 587), compared with noncarriers (n = 48,149), had a 6% and 1% reduction in predicted percentage of forced vital capacity (FVC % predicted) (P = 0.05) and a nonsignificant 7% and 1% reduction in predicted percentage of forced expiratory volume in one second (FEV(1) % predicted) (P = 0.06), respectively. The Arg293X genotype interacted with gender (P = 0.004) and α(1) -antitrypsin MZ heterozygosity (P = 0.049), but not with superoxide dismutase-3 E1I1 heterozygosity (P = 0.11) in determining FEV(1) % predicted. Amongst men, FEV(1) % predicted and FVC % predicted were both reduced by 4% (P = 0.0004 and P = 0.0003, respectively) in Arg293X heterozygotes compared with noncarriers. Corresponding values were 14% (P = 0.03) and 11% (P = 0.04) amongst MZ heterozygotes, and 9% (P = 0.03) and 8% (P = 0.04) amongst E1I1 heterozygotes, compared with noncarriers. Lung function did not differ between Arg293X heterozygotes and noncarriers amongst females or individuals without MZ and E1I1. Arg293X heterozygosity was associated with spirometry-defined COPD amongst men [odds ratio (95% confidence interval): 1.7 (1.1-2.4)], but not with COPD in the whole cohort or in any other subgroup. CONCLUSIONS SRAI/II Arg293X heterozygotes have reduced lung function and increased COPD risk amongst men. They also have reduced lung function amongst individuals heterozygous for the α(1)-antitrypsin MZ and superoxide dismutase-3 E1I1 genotypes.