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Our goal is to enhance the ability to differentiate normal lung from subtle pathologies via multidetector row CT (MDCT) by extending a two-dimensional (2-D) texturebased tissue classification [adaptive multiple feature method (AMFM)] to use three-dimensional (3-D) texture features. We performed MDCT on 34 humans and classified volumes of interest (VOIs) in the MDCT images into five categories: EC, emphysema in severe chronic obstructive pulmonary disease (COPD); MC, mild emphysema in mild COPD; NC, normal appearing lung in mild COPD; NN, normal appearing lung in normal nonsmokers; and NS, normal appearing lung in normal smokers. COPD severity was based upon pulmonary function tests (PFTs). Airways and vessels were excluded from VOIs; 24 3-D texture features were calculated; and a Bayesian classifier was used for discrimination. A leave-one-out method was employed for validation. Sensitivity of the four-class classification in the form of 3-D/2-D was: EC: 85%/71%, MC: 90%/82%; NC: 88%/50%; NN: 100%/60%. Sensitivity and specificity for NN using a two-class classification of NN and NS in the form of 3-D/2-D were: 99%/72% and 100%/75%, respectively. We conclude that 3-D AMFM analysis of lung parenchyma improves discrimination compared to 2-D AMFM of the same VOIs. Furthermore, our results suggest that the 3-D AMFM may provide a means of discriminating subtle differences between smokers and nonsmokers both with normal PFTs.