A prostate computer-aided diagnosis (CAD) based on random forest to detect prostate cancer using a combination of spatial, intensity, and texture features extracted from three sequences, T2W, ADC, and B2000 images, is proposed. The random forest training considers instance-level weighting for equal treatment of small and large cancerous lesions as well as small and large prostate backgrounds. Two other approaches, based on an AutoContext pipeline intended to make better use of sequence-specific patterns, were considered. One pipeline uses random forest on individual sequences while the other uses an image filter described to produce probability map-like images. These were compared to a previously published CAD approach based on support vector machine (SVM) evaluated on the same data. The random forest, features, sampling strategy, and instance-level weighting improve prostate cancer detection performance [area under the curve (AUC) 0.93] in comparison to SVM (AUC 0.86) on the same test data. Using a simple image filtering technique as a first-stage detector to highlight likely regions of prostate cancer helps with learning stability over using a learning-based approach owing to visibility and ambiguity of annotations in each sequence.