This paper explored the hidden biomedical information from knee magnetic resonance (MR) images for osteoarthritis (OA) prediction. We have computed the cartilage damage index (CDI) information from 36 informative locations on tibiofemoral cartilage compartment from 3-D MR imaging and used principal component analysis (PCA) analysis to process the feature set. Four machine learning methods (artificial neural network (ANN), support vector machine, random forest, and naïve Bayes) were employed to predict the progression of OA, which was measured by the change of Kellgren and Lawrence (KL) grade, Joint Space Narrowing on Medial compartment (JSM) grade, and Joint Space Narrowing on Lateral compartment (JSL) grade. To examine the different effects of medial and lateral informative locations, we have divided the 36-D feature set into a 18-D medial feature set and a 18-D lateral feature set and run the experiment on four classifiers separately. Experiment results showed that the medial feature set generated better prediction performance than the lateral feature set, while using the total 36-D feature set generated the best. PCA analysis is helpful in feature space reduction and performance improvement. For KL grade prediction, the best performance was achieved by ANN with AUC = 0.761 and F-measure = 0.714. For JSM grade prediction, the best performance was achieved by random forest with AUC = 0.785 and F-measure = 0.743, while for JSL grade prediction, the best performance was achieved by ANN with AUC = 0.695 and F-measure = 0.796. As experiment results showing that the informative locations on medial compartment provide more distinguishing features than informative locations on the lateral compartment, it could be considered to select more points from the medial compartment while reducing the number of points from the lateral compartment to improve clinical CDI design.