In patients with airflow limitation caused by cigarette smoking, lung density measured by computed tomography is strongly correlated with quantitative pathology scores of emphysema, but the ability of lung densitometry to detect progression of emphysema is disputed. We assessed the sensitivity of lung densitometry as a parameter of disease progression of emphysema in comparison to FEV(1) and gas transfer. At study baseline and after 30 months we measured computed tomography (CT)-derived lung density, spirometry and carbon monoxide diffusion coefficient in 144 patients with chronic obstructive pulmonary disease (COPD) in five different centers. Annual change in lung density was 1.31 g/L/year (CI 95%: -2.12 to -0.50 HU, p=0.0015, 39.5 mL/year (CI 95%: -100.0-21.0 mL, p=0.2) for FEV(1) (-39.5 mL) and 24.3 micromol/min/kPa/L/year for gas transfer (CI 95%: -61.0-12.5 micromol/min/kPa/L/year, p=0.2). Signal-to-noise ratio (mean change divided by standard error of the change) for the detection of annual change was 3.2 for lung densitometry, but 1.3 for both FEV(1) and gas diffusion. We conclude that detection of progression of emphysema was found to be 2.5-fold more sensitive using lung densitometry than by using currently recommended lung function parameters. Our results support CT scan as an efficacious test for novel drugs for emphysema.