Multidisciplinary and collaborative approaches are crucial for identifying novel susceptibility genes for chronic obstructive pulmonary disease (COPD). We integrated results from murine and human gene expression microarray studies of lung tissue with whole genome–scan linkage results, selecting SERPINE2 for investigation in COPD. SERPINE2 is located on chromosome 2q33-35, a genomic region linked to COPD phenotypes. In the Boston Early-Onset COPD Study, we genotyped 48 single nucleotide polymorphisms (SNPs) in SERPINE2 and performed association analysis with spirometric phenotypes in 127 severe, early-onset COPD pedigrees. Using the family-based association test implemented in the Pedigree-Based Association Test (PBAT) and incorporating a gene-by-smoking interaction term, we observed significant association of quantitative COPD phenotypes and 11 SNPs in SERPINE2 (p values ranging between 0.002 and 0.05). Association of 8 of these 11 SERPINE2 variants was replicated in a case-control association analysis of COPD cases from the National Emphysema Treatment Trial and smoking controls with normal spirometry from the Normative Aging Study. Haplotype analysis in the case-control study demonstrated the strong association with an 8-SNP haplotype block that included exons 2 and 3 of the SERPINE2 gene (p = 0.008). Using expression array analysis in murine models, we have prioritized candidate gene selection and have demonstrated association and replication of SERPINE2 as a potential COPD susceptibility gene.