Rationale: Cachexia, whether assessed by body mass index (BMI) or fat free mass index (FFMI), affects a significant proportion of patients with chronic obstructive pulmonary disease (COPD) and is an independent risk factor for increased mortality, increased emphysema, and more severe airflow obstruction. The variable development of cachexia among COPD patients suggests a role for genetic susceptibility. Objective: To determine genetic susceptibility loci involved in the development of low body mass and fat free mass index in COPD subjects Methods: A genome-wide association study of BMI was conducted in three independent cohorts of European descent with GOLD Stage II or higher COPD: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE, n=1734), Norway-Bergen cohort (n=851), and a subset of subjects from the National Emphysema Treatment Trial (NETT, n=365). A genome-wide association of FFMI was conducted in two of the cohorts (ECLIPSE and Norway). Measurements and Main Results: In the combined analyses, a significant association was found between rs8050136, located in the first intron of the fat mass and obesity associated (FTO) gene, and BMI (p = 4.97 x 10-7) and FFMI (p = 1.19 x 10-7). We replicated the association in a fourth, independent cohort consisting of 502 COPD subjects from COPDGene (p = 6 x 10-3). Within the largest contributing cohort of our analysis, lung function, as assessed by forced expiratory volume in the first second (FEV1), varied significantly by FTO genotype. Conclusions: Our analysis suggests a potential role for the FTO locus in the determination of anthropomorphic measures associated with COPD.