Accurate detection of diffuse lung disease is an important step for computerized diagnosis and quantification of this disease. It is also a difficult clinical task for radiologists. We developed a computerized scheme to assist radiologists in the detection of diffuse lung disease in multi-detector computed tomography (CT). Two radiologists selected 31 normal and 37 abnormal CT scans with ground glass opacity, reticular, honeycombing and nodular disease patterns based on clinical reports. The abnormal cases in our database must contain at least an abnormal area with a severity of moderate or severe level that was subjectively rated by the radiologists. Because statistical texture features may lack the power to distinguish a nodular pattern from a normal pattern, the abnormal cases that contain only a nodular pattern were excluded. The areas that included specific abnormal patterns in the selected CT images were then delineated as reference standards by an expert chest radiologist. The lungs were first segmented in each slice by use of a thresholding technique, and then divided into contiguous volumes of interest (VOIs) with a 64 × 64 × 64 matrix size. For each VOI, we determined and employed statistical texture features, such as run-length and co-occurrence matrix features, to distinguish abnormal from normal lung parenchyma. In particular, we developed new run-length texture features with clear physical meanings to considerably improve the accuracy of our detection scheme. A quadratic classifier was employed for distinguishing between normal and abnormal VOIs by the use of a leave-one-case-out validation scheme. A rule-based criterion was employed to further determine whether a case was normal or abnormal. We investigated the impact of new and conventional texture features, VOI size and the dimensionality for regions of interest on detecting diffuse lung disease. When we employed new texture features for 3D VOIs of 64 × 64 × 64 voxels, our system achieved the highest performance level: a sensitivity of 86% and a specificity of 90% for the detection of abnormal VOIs, and a sensitivity of 89% and a specificity of 90% for the detection of abnormal cases. Our computerized scheme would be useful for assisting radiologists in the diagnosis of diffuse lung disease.