Abstract Background Chronic Obstructive Pulmonary Disease (COPD) has significant systemic effects beyond the lungs amongst which muscle wasting is a prominent contributor to exercise limitation and an independent predictor of morbidity and mortality. The molecular mechanisms leading to skeletal muscle dysfunction/wasting are not fully understood and are likely to be multi-factorial. The need to develop therapeutic strategies aimed at improving skeletal muscle dysfunction/wasting requires a better understanding of the molecular mechanisms responsible for these abnormalities. Microarrays are powerful tools that allow the investigation of the expression of thousands of genes, virtually the whole genome, simultaneously. We aim at identifying genes and molecular pathways involved in skeletal muscle wasting in COPD. Methods We assessed and compared the vastus lateralis transcriptome of COPD patients with low fat free mass index (FFMI) as a surrogate of muscle mass (COPD L ) (FEV 1 30 ± 3.6%pred, FFMI 15 ± 0.2 Kg.m −2 ) with patients with COPD and normal FFMI (COPD N ) (FEV 1 44 ± 5.8%pred, FFMI 19 ± 0.5 Kg.m −2 ) and a group of age and sex matched healthy controls (C) (FEV 1 95 ± 3.9%pred, FFMI 20 ± 0.8 Kg.m −2 ) using Agilent Human Whole Genome 4x44K microarrays. The altered expression of several of these genes was confirmed by real time TaqMan PCR. Protein levels of P21 were assessed by immunoblotting. Results A subset of 42 genes was differentially expressed in COPD L in comparison to both COPD N and C (PFP