Rationale: Previously reported linkage to forced expiratory volume in 1 second (FEV₁) (LOD score = 5.0) on 6q27 in the Framingham Heart Study (FHS) led us to explore a candidate gene, SMOC2, at 168.6 Mb. Objectives: We tested association between SMOC2 polymorphisms and FEV₁ and forced vital capacity (FVC) in unrelated FHS participants. Methods: Twenty single nucleotide polymorphisms(SNPs) around SMOC2 were genotyped in 1734 subjects. Measurements and Main Results: SNP data were analyzed using multiple linear regression models incorporating gender, age, body mass index, height, and smoking history as covariates, and analyses were repeated within strata of ever and never smokers. The minor allele of SNP rs1402 was associated with higher mean FEV₁ (P = 0.003) and FVC (P = 0.02) measures. In never-smoking subjects, association to higher measures was observed with the minor allele of rs747995 (FEV₁ P = 0.0006; FVC P = 0.0008). These two SNPs lie in different haplotype blocks and reside in intron-4 of SMOC2. Haplotype analysis revealed a common G-T haplotype (rs747995-rs1402) with 77% frequency in never-smoking FHS subjects. The G-T haplotype was associated with reduction of 126 mL for FEV₁ (P = 0.0002), and 157 mL for FVC (P = 0.0002). The G-T haplotype was similarly associated in a set of never-smoking subjects from the Family Heart Study, FEV₁ (P = 0.03) and FVC (P = 0.03). Conclusions: The replication of the association in two populations supports the possibility that SMOC2 might play an important role in the determination of FEV₁ and FVC.