Image-guided therapies in the abdomen and pelvis are often hindered by motion artifacts in cone-beam CT (CBCT) arising from complex, non-periodic, deformable organ motion during long scan times (5-30 s). We propose a deformable image-based motion compensation method to address these challenges and improve CBCT guidance. Motion compensation is achieved by selecting a set of small regions of interest in the uncompensated image to minimize a cost function consisting of an autofocus objective and spatiotemporal regularization penalties. Motion trajectories are estimated using an iterative optimization algorithm (CMA-ES) and used to interpolate a 4D spatiotemporal motion vector field. The motion-compensated image is reconstructed using a modified filtered backprojection approach. Being image-based, the method does not require additional input besides the raw CBCT projection data and system geometry that are used for image reconstruction. Experimental studies investigated: (1) various autofocus objective functions, analyzed using a digital phantom with a range of sinusoidal motion magnitude (4, 8, 12, 16, 20 mm); (2) spatiotemporal regularization, studied using a CT dataset from The Cancer Imaging Archive with deformable sinusoidal motion of variable magnitude (10, 15, 20, 25 mm); and (3) performance in complex anatomy, evaluated in cadavers undergoing simple and complex motion imaged on a CBCT-capable mobile C-arm system (Cios Spin 3D, Siemens Healthineers, Forchheim, Germany). Gradient entropy was found to be the best autofocus objective for soft-tissue CBCT, increasing structural similarity (SSIM) by 42%-92% over the range of motion magnitudes investigated. The optimal temporal regularization strength was found to vary widely (0.5-5 mm-2) over the range of motion magnitudes investigated, whereas optimal spatial regularization strength was relatively constant (0.1). In cadaver studies, deformable motion compensation was shown to improve local SSIM by ∼17% for simple motion and ∼21% for complex motion and provided strong visual improvement of motion artifacts (reduction of blurring and streaks and improved visibility of soft-tissue edges). The studies demonstrate the robustness of deformable motion compensation to a range of motion magnitudes, frequencies, and other factors (e.g. truncation and scatter).