This study aims to develop and evaluate a new computer-aided diagnosis (CADx) scheme based on analysis of global mammographic image features to predict likelihood of cases being malignant. An image dataset involving 1,959 cases was retrospectively assembled. Suspicious lesions were detected and biopsied in each case. Among them, 737 cases are malignant and 1,222 are benign. Each case includes four mammograms of craniocaudal and mediolateral oblique view of left and right breasts. CADx scheme is applied to pre-process mammograms, generate two image maps in frequency domain using discrete cosine transform and fast Fourier transform, compute bilateral image feature differences from left and right breasts, and apply a support vector machine (SVM) to predict likelihood of the case being malignant. Three sub-groups of image features were computed from the original mammograms and two transformation maps. Four SVMs using three sub-groups of image features and fusion of all features were trained and tested using a 10-fold cross-validation method. The computed areas under receiver operating characteristic curves (AUCs) range from 0.85 to 0.91 using image features computed from one of three sub-groups, respectively. By fusion of all image features computed in three sub-groups, the fourth SVM yields a significantly higher performance with AUC = 0.96±0.01 (p<0.01). This study demonstrates feasibility of developing a new global image feature analysis based CADx scheme of mammograms with high performance. By avoiding difficulty and possible errors in breast lesion segmentation, this new CADx approach is more efficient in development and potentially more robust in future application.