Microaneurysms are regarded as the first signs of diabetic retinopathy (DR), but the microaneurysms are not clear in the color retinal images, and many researches were studied to detect and locate these lesions. In this paper, a new hierarchical computing-aided diagnosis approach is proposed for the microaneurysms detection by using the multi-scale and multi-orientation sum of matched filter (MMMF) and machine learning, where 37 dimensional features are extracted from each candidate. Furthermore, several classifiers such as the k-nearest neighbor (kNN), local linear discrimination analysis (LLDA) and support vector machine (SVM) are modified to distinguish the true microaneurysms from the false ones, which is a typical unbalanced classification problem. The effectiveness of the proposed method is verified through the training set of a publicly available database, and the experiment results show that the proposed method has better detection performance including the receiver operating characteristic (ROC) curve and the free-response receiver operating characteristic (FROC) curve. Moreover, the proposed method with 37 dimensional features outperforms that with other features and has a sensitivity from 1/8 to 8 with the average of all seven points being 0.286 tested on the same database.