This paper proposes a novel method of using regressionguided deformable models for brain regions of interest (ROIs) segmentation. Different from conventional deformable segmentation, which often deforms shape model locally and thus sensitive to initialization, we propose to learn a regressor to explicitly guide the shape deformation, thus eventually improves the performance of ROI segmentation. The regressor is learned via two steps, (1) a joint classification and regression random forest (CRRF) and (2) an auto-context model. The CRRF predicts each voxel’s deformation to the nearest point on the ROI boundary as well as each voxel’s class label (e.g., ROI versus background). The auto-context model further refines all voxel’s deformations (i.e., deformation field) and class labels (i.e., label maps) by considering the neighboring structures. Compared to the conventional random forest regressor, the proposed regressor provides more accurate deformation field estimation and thus more robust in guiding deformation of the shape model. Validated in segmentation of 14 midbrain ROIs from the IXI dataset, our method outperforms the state-of-art multi-atlas label fusion and classification methods, and also significantly reduces the computation cost.