BACKGROUND: Emphysema is a key contributor to airflow limitation in obstructive pulmonary disease (COPD) and can be quantified using CT investigated the change in CT lung density in a longitudinal, cohort of patients with COPD. We also explored the potential relation emphysema and patient characteristics, and investigated if certain biomarkers were associated with decline in CT lung density. METHODS: We random coefficient model to assess predictors of both CT lung density longitudinal change over 3 years in 1928 patients with COPD enrolled in Evaluation of COPD Longitudinally to Identify Predictive Surrogate (ECLIPSE) study. Lung density was measured for every voxel in the CT after correcting for lung volume was expressed as the density at lowest percentile point of the distribution. This study is registered with ClinicalTrials.gov, number NCT00292552. FINDINGS: Lung density at influenced by age, sex, body-mass index, current smoking status and history, and severity of airflow limitation. The observed decline in was variable (mean decline -1.13 g/L [SE 0.06] per year). The annual lung density was more rapid in women (additional -0.41 [SE 0.14] g/L per p=0.003) than men and in current smokers (additional -0.29 [SE 0.14] g/L year, p=0.047) than in former smokers. Circulating levels of the surfactant protein D (SP-D) and soluble receptor for advanced glycation endproduct (sRAGE) were significantly associated with both baseline lung and its decline over time. INTERPRETATION: This study shows that decline density in COPD can be measured, that it is variable, and related to gender. We identified potential biochemical predictors of the presence progression of emphysema. FUNDING: GlaxoSmithKline.