Bulky (>10cm) soft tissue (STS) and osteosarcomas (OSS) have relatively poor local control rates compared to smaller lesions when treated with standard neoadjuvant radiotherapy (RT) and wide local excision. Pathologic response rates (pCR ≥80% necrosis) in STS/OS have been correlated with improved clinical outcomes, including survival. Spatially Fractionated GRID RT (SFGRT) has been utilized in the megavoltage era as a safe, noninvasive form of dose-escalation that has been aptly likened to an external beam form of brachytherapy based on dose distribution and dose per fraction. We hypothesized that SFGRT followed by standard of care neoadjuvant RT would improve pathologic response rates over historical controls without increased complications. Our institutional standard approach for very high-risk, bulky sarcomas has been to deliver a single fraction of SFGRT (15 Gy) followed immediately by conventionally fractionated RT (CRT) in the neoadjuvant setting. On an IRB-approved protocol, we retrospectively reviewed demographics, histology, treatment characteristics, clinical outcomes, toxicity, and pathologic response rates for patients receiving this regimen. All pathologic response rates were formally reviewed by an expert pathologist. Since 2005, 21 patients have received single fraction SFGRT (15 Gy) followed by CRT (range 45-50.4 Gy, 1.8-2.25 Gy/fx) prior to oncologic resection. Median tumor size was 14.4 cm (range, 9.7-40cm; mean, 16.0cm) in greatest dimension. Histologies included pleomorphic (n=7), leiomyosarcoma (n=2), myxofibrosarcoma (n=3), liposarcoma (n=3), spindle cell (n=1), extraskeletal OSS (n=2), OSS (n=2), and chondrosarcoma (CS) (n=1) (TOTAL: 16 STS, 4 OSS, 1 CS). Nineteen were high-grade, while 2 were low-grade. Four patients received neoadjuvant chemotherapy with 3 having progression/poor response prior to RT. Fifteen patients (71%) had negative resection margins, and 6 had positive margins. With a median follow-up of 33 months, 4 (19.0%) patients have failed locoregionally, 6 (29%) patients have progressed, and 7 (33%) have died. For 20 patients, expert pathologic review was possible. Seven (35.0%) patients achieved a pCR. The two low grade tumors had 0% response; 1 CS, 50%. High-grade STS demonstrated a 39% (5/13) pCR rate, and OSS, 50% (2/4). Five (24%) patients developed a major wound complication per NCIC standards. SFGRT+CRT is a safe and effective neoadjuvant regimen for very high-risk STS/OSS. Pathologic response rates in this institutional series exceed those seen with Chemo-RT and CRT alone on prospective trials (RTOG 9514/0630) despite larger tumors. Further prospective evaluation is warranted.