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This study developed a computer-aided detection (CAD) scheme for pulmonary embolism (PE) detection and investigated several approaches to improve CAD performance. In the study, 20 computed tomography examinations with various lung diseases were selected, which include 44 verified PE lesions. The proposed CAD scheme consists of five basic steps: 1) lung segmentation; 2) PE candidate extraction using an intensity mask and tobogganing region growing; 3) PE candidate feature extraction; 4) false-positive (FP) reduction using an artificial neural network (ANN); and 5) a multifeature-based k-nearest neighbor for positive/negative classification. In this study, we also investigated the following additional methods to improve CAD performance: 1) grouping 2-D detected features into a single 3-D object; 2) selecting features with a genetic algorithm (GA); and 3) limiting the number of allowed suspicious lesions to be cued in one examination. The results showed that 1) CAD scheme using tobogganing, an ANN, and grouping method achieved the maximum detection sensitivity of 79.2%; 2) the maximum scoring method achieved the superior performance over other scoring fusion methods; 3) GA was able to delete “redundant” features and further improve CAD performance; and 4) limiting the maximum number of cued lesions in an examination reduced FP rate by 5.3 times. Combining these approaches, CAD scheme achieved 63.2% detection sensitivity with 18.4 FP lesions per examination. The study suggested that performance of CAD schemes for PE detection depends on many factors that include 1) optimizing the 2-D region grouping and scoring methods; 2) selecting the optimal feature set; and 3) limiting the number of allowed cueing lesions per examination.