The primary objective of this study was to develop and validate simultaneous PET/MRI-MRS as a novel biological image-guided approach to neoadjuvant radiotherapy (RT) and/or chemoradiation (chemoRT) in soft tissue sarcomas (STS). A patient with sarcoma of the right thigh underwent PET/MRI scan before and after neoadjuvant (preoperative) radiotherapy. The magnetic resonance imaging (MRI) and 2-deoxy-2-[fluorine-18]-fluoro-D-glucose-Positron Emission Tomography (18F-FDG-PET) scans were performed simultaneously. In the post-radiation scan, magnetic resonance spectroscopy (MRS) was subsequently acquired with volume of interest positioned in a residual hyper-metabolic region detected by PET. Post-radiation PET/MRI showed a residual T2-hyperintense mass with significantly reduced 18F-FDG-uptake, compatible with near complete response to radiotherapy. However, a small region of residual high 18F-FDG uptake was detected at the tumor margin. MRS of this region had similar metabolite profile as normal tissue, and was thus considered false positive on PET scan. Pathology results were obtained after surgery for confirmation of imaging findings.