Background: Preclinical studies suggest that VEGF blockade can have a role in the preoperative treatment of rectal cancer but how to combine it with chemotherapy (CT) and/or CRT remains controversial. Increased risk of postoperative morbidity has been reported with preop anti VEGF/CRT combination. Aflibercept (Afli) acts as a soluble receptor that binds to human VEGF-A, VEGF-B, PlGF. We hypothesized that administering Afli/FOLFOX followed by CRT would improve pathological complete response (pCR) without compromising wound healing. Methods: Between 1/2015-3/2017, pts selected with centrally reviewed magnetic resonance (mr) imaging with middle or distal third, mrT3/T4/N2 rectal adenocarcinoma were randomly assigned (2:1, stratified by mr extra-mural venous invasion and mrT4) to mFOLFOX6 with (arm 1) or without Afli (arm 2) prior to standard CRT (capecitabine with 50.4 Gy in 28 fractions) and TME. The study was designed to perform a hypothesis testing with an alpha = .2 and beta = .2. Due to two planned interim analyses (O´Brien), the threshold for statistical significance was p < 0.1984 in the final analysis. We present primary (pCR) and early secondary endpoints: acute toxicity and compliance. Results: 115/65 pts were assigned to arm 1/arm 2. The pCR rate (ypT0N0) in pts who underwent curative surgery was achieved in 25/103: 24.2%; (95% CI 16.36-33.71) in arm 1 and in 9/62: 14.5% (CI 6.86-25.78) in arm 2. p = 0.1335 Preoperative grade 3-4 toxicity occurred in 50% in arm 1 and 23% in arm 2 during the I period (difference mostly due to hypertension). Overall postoperative complications were similar between both arms (14.7% and 12.3%). Six cycles of I CT were administered in 92% and 95% and 90% and 96% completed CRT in arm 1 and 2 respectively. R0 resection rate was 87.3% and 88.7%. Conclusions: The addition of aflibercept to I mFOLFOX6 led to a significantly greater pCR rate compared with mFOLFOX6 alone in patients with high-risk rectal cancer. The experimental arm showed higher toxicity during the I phase, with similar toxicity afterwards and no increase in surgical complications. Funding: Sanofi Clinical trial information: NCT02340949.