Background: Current chemotherapy regimens used during chemoradiation (CRT) are adequate for radiosensitization but suboptimal for systemic control. The aim of this study was to assess tolerability, and local/systemic benefits of a new regimen delivering intensive chemotherapy plus bevacizumab (Bev) and radical radiotherapy in an interdigitating manner. Methods: Phase II study for patients (pts) with untreated simultaneous symptomatic primary & metastatic rectal cancer. Pts received, in 12 weeks, 3 courses of FOLFOX-Bev and pelvic radiation 50.4Gy with concurrent Oxaliplatin/5-FU/Bev. A) FOLFOX chemotherapy: Oxaliplatin (Ox) 100mg/m², Leucovorin 200mg/m², 5FU 400mg/m² bolus, all day 1, and 5FU CI 2.4g/m²/46 hours given in weeks 1, 6, and 11. B) Bev 5mg/kg in weeks 1, 3, 5, 9, 11. C) Pelvic CRT: 25.2Gy in 3 weeks, 1.8Gy/fr, with concurrent Ox 85mg/m² day 1 and 5FU CI 200mg/m²/day given in weeks 3-5, and 8-10. All pts staged with CT, MRI and FDG-PET before and post treatment. The primary endpoint was tolerability. Results: 30 pts treated. The mean age: 57 years. Rectal primary MRI stages: T2 3%, T3 73% and T4 24%. All pts had metastasis: liver 80%, lung 10%. 42% of pts had ≥ 3 sites of metastatic disease. 24 pts (80%) completed the 12 week treatment regimen and the planned radiation dose. Overall 80% of pts received the planned number of Ox courses. 77% and 80% of pts received ≥ 75% of protocol Ox and Bev dose. Treatment related grade (Gr) 3 toxicities were: neutropenia 40%, diarrhea 7%, radiation perineal skin reaction 13%, 1 patient each with hypertension and enterocolits. Gr 4 neutropenia in 23%. Febrile neutropenia in 3 (10%) pts, no septic deaths. The overall CT/MRI response rates for rectal primary and metastatic disease were 62% and 48% respectively. The PET metabolic response rate for rectal primary (CR+PR) was 100% (CR 39%) and for metastatic disease 90% (CR 21%). Conclusions: It is feasible to deliver intensive chemotherapy plus bevacizumab and radical radiotherapy in an interdigitating manner treating both primary and metastatic rectal cancer simultaneously. High response rates are encouraging. This treatment design warrants further investigations. Clinical trial information: ACTRN12611000033943.