Wireless capsule endoscopy (WCE) is an effective video technology to diagnose gastrointestinal (GI) diseases, such as bleeding, ulcer, and tumor. In order to avoid a tedious manual review process of long duration WCE video recordings, automatic disease detection schemes have received significant attention from the researchers. In particular, instead of the conventional approach of dealing with a single disease, developing a unified scheme, which is capable of detecting multiple GI diseases, is getting more importance while being challenging. In this paper, a unified computer-aided scheme is developed for detecting multiple GI diseases from WCE videos based on a proposed least-square saliency transformation (LSST) followed by a probabilistic model-fitting approach. Commonly in the training phase, image-level labeling of images is used, as pixel-level annotations are available only for a small number of images. In view of utilizing the knowledge from pixel-level annotated diseased images, an LSST scheme is proposed to extract a set of optimum prior coefficient-vectors which is later used to capture the salient pixels of interest (POI) in a larger WCE image dataset that do not have pixel-annotations. The intensity distributions of salient POI are modeled by a suitable probability density function (PDF) and the fitted PDF parameters are utilized as features in the proposed supervised hierarchical classification scheme. A large number of WCE images obtained from publicly available WCE videos are used for performance evaluation and it is found that the result obtained by the proposed method outperforms the results obtained in case of some state-of-the-art methods. INDEX TERMS Multiple gastrointestinal disease detection, K-means clustering, least square saliency transformation, quadratic programming, support vector machine. The associate editor coordinating the review of this manuscript and approving it for publication was Derek Abbott. as bleeding is the most common GI disease [3]-[14]. The reported automatic bleeding detection schemes are mainly based on suspected blood indicator [3], histogram-based features [4]-[7], statistical features [8], block-based approaches [7], [9], features from salient points [11], [15] and deep learning framework [12]. In [14], the active and inactive bleeding subgroups are classified based on histogram features and then, separately fed to different fully connected neural networks for bleeding region segmentation. On the other side, automatic ulcer detection schemes are proposed based on convolutional neural network (CNN) based architecture [16], completed local binary patterns (LBP), and laplacian