To prospectively assess the efficacy and toxicity of External Beam Radiotherapy (EBRT) reirradiation in patients (pts) with Malignant Spinal Cord Compression (MSCC) occurring in previously irradiated area and not for surgical decompression. An ICH-GCP compliant prospective Gehan’s two-stage design Phase 2 trial evaluated a radiobiology based EBRT reirradiation strategy for MSCC. The primary endpoint was mobility (Tomita mobility score change at 5 weeks); the secondary endpoints were long-term spinal toxicity & Radiation-Induced Myelopathy (RIM) (RTOG SOMA scale), Quality of Life (EORTC-QLQ-C15 PAL v. 1.0) and non-spinal acute & long-term toxicity (RTOG scale). Eligible pts had a pathological proven malignancy, excluding primary bone tumor, and diagnosed with a treatment naïve MRI documented MSCC, occurring in a previously irradiated spinal area (Spinal dose received ≤ 90 Gy2). Based on radiobiological and retrospective clinical data, pts were classified into 3 RIM risk categories. The reirradiation EBRT schedule aimed to deliver a minimum of 12 Gy in 4 fractions (Maximum: 30 Gy/10), and a cumulative dose to the spine (equal to the BED sum of each radiotherapy courses prescribed doses) of respectively 100 Gy2, if time interval ≤ 6 months between radiotherapy courses, and 130 Gy2, if > 6 months. From 01/2008 to 09/2016, 22 pts were recruited, 16 pts with week 1 acute toxicity data and 11 pts with week 5 efficacy data (Early death: 9, withdrew consent: 2). Baseline population characteristics were: median age: 66 years (24-88), ♀/♂ratio: 6/16, median KPS: 60 (40-100). 16 pts were initially ambulatory and all were within the low risk RIM category. The common pathologies were prostate (36%) and lung cancer (23%). The compression levels were cervical (9.1%), thoracic (68.2%), lumbar (13.6%) and lumbo-sacral (9.1%). The week 5 overall response rate, defined as improved (n = 2) or stable (n = 7) Tomita score, was 81.8 % (95% CI: 52.3-94.9%), largely above the 20% protocol-defined clinical efficacy futility mark, and associated at week 5 with a significant improvement of the EORTC QLQ-C15-PAL pain score (28.6 units, 95% CI 0.8 to 56.3) and a non-significant improvement of Physical Functioning score. The median survival from consent date was 2.2 months (0.9-5.4). Acute toxicity was observed in 9 pts, all grade ≤ 2. Among the 8 pts reaching the 3 month assessment or more, there were 3 grade 1 late-toxicity events (2 intestine and 1 fatigue) and 2 SOMA grade> 2 RIM (diagnosed at 3 & 12 months) , corresponding to an overall cumulative incidence estimated between 9.1 % ( intention to treat) and 25% (actual), exceeding the 3% risk predicted by the radiobiological and clinical models. EBRT reirradiation provides similar response rate than the one reported in our previously reported trial with irradiation naïve MSCC pts, but the observed RIM incidence was higher than predicted, demonstrating the importance of prospective trials.