We describe a multimodality imaging approach that combines x-ray tomosynthesis with near-infrared diffuse optical tomography (DOT) for high-resolution imaging of osteoarthritis in the finger joints. In this approach, we take advantage of high resolution x-ray imaging particularly of the bones and incorporate the fine structural maps obtained from x ray as a priori information into DOT reconstructions. To realize this multi-modality approach, we constructed a hybrid imaging platform that integrated a C-arm–based x-ray tomosynthetic system with a multichannel optic-fiber–based DOT system. We also implemented improved hybrid regularization-based reconstruction algorithms that have shown to be especially effective for high-resolution modality-guided DOT. Initial evaluation of our x-ray–guided DOT reconstruction approach in the finger joints shows that spatial resolution of DOT can be enhanced dramatically when the three-dimensional geometry of bones is known a priori. In particular, the improved quantitative capability of imaging absorption and scattering coefficients of the joint tissues allows for more accurate diagnosis of osteoarthritis over x-ray radiography or DOT alone.