ABSTRACT: Quantitative multidetector computed tomography (MDCT) as a potential biomarker is increasingly used for severity assessment of emphysema in chronic obstructive pulmonary disease (COPD). Aim of this study was to evaluate the user-independent measurement variability between five different fully-automatic densitometry software tools.MDCT and full-body plethysmography incl. forced expiratory volume in 1s and total lung capacity were available for 49 patients with advanced COPD (age?=?64±9 years, forced expiratory volume in 1 s?=?31±6% predicted). Measurement variation regarding lung volume, emphysema volume, emphysema index, and mean lung density was evaluated for two scientific and three commercially available lung densitometry software tools designed to analyze MDCT from different scanner types.One scientific tool and one commercial tool failed to process most or all datasets, respectively, and were excluded. One scientific and another commercial tool analyzed 49, the remaining commercial tool 30 datasets. Lung volume, emphysema volume, emphysema index and mean lung density were significantly different amongst these three tools (p<0.001). Limits of agreement for lung volume were [-0.195, -0.052 l], [-0.305, -0.131 l], and [-0.123, -0.052 l] with correlation coefficients of r?=?1.00 each. Limits of agreement for emphysema index were [-6.2, 2.9%], [-27.0, 16.9%], and [-25.5, 18.8%], with r?=?0.79 to 0.98. Correlation of lung volume with total lung capacity was good to excellent (r?=?0.77 to 0.91, p<0.001), but segmented lung volume (6.7±1.3-6.8±1.3 l) were significantly lower than total lung capacity (7.7±1.7 l, p<0.001).Technical incompatibilities hindered evaluation of two of five tools. The remaining three showed significant measurement variation for emphysema, hampering quantitative MDCT as a biomarker in COPD. Follow-up studies should currently use identical software, and standardization efforts should encompass software as well.