Risk for Chronic Obstructive Pulmonary Disease (COPD) is determined by both cigarette smoking and genetic susceptibility, but little is known about gene-by-smoking interactions. We performed a genome-wide association analysis of 179,689 controls and 21,077 COPD cases from UK Biobank subjects of European ancestry recruited from 2006 to 2010, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degree-of-freedom test) as well as interaction effects alone (1-degree-of-freedom interaction test). We sought to replicate significant results in the COPDGene study and SpiroMeta Consortium. We considered two smoking variables: (1) ever/never and (2) current/non-current. In the 1-degree-of-freedom interaction test, we identified one genome-wide significant locus on 15q25.1 (CHRNB4) for ever- and current-smoking and identified PI*Z allele (rs28929474) of SERPINA1 for ever-smoking and 3q26.2 (MECOM) for current-smoking in an analysis of previously reported COPD loci. In the 2-degree-of-freedom test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (SMPD3) and 19q13.2 (EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, were replicated in the COPDGene and SpiroMeta. We identified interaction effects at previously reported COPD loci, however, we failed to identify novel susceptibility loci.