Despite considerable progress in hematological malignancies (HM) biology during the last decades, translation into clinical benefit remains a major challenge. To improve patient selection and identify patients most likely to benefit from phase I trials, we designed and validated, in an independent cohort, a simple prognostic score. Treatment outcome, toxicity, and survival data from 82 consecutive patients enrolled in 14 phase I trials were reviewed (January 2008–February 2012). We validated these results on a prospectively collected cohort (17 phase I trials, February 2012–May 2014, 88 patients). Within a median follow-up of 19.1 months (range: 2.1–43.8 months), the median progression-free and overall survival (OS) were, respectively, 4.1 months [95% confidence interval (CI): 3.0–5.3] and 19.8 months (95% CI: 16.1–36.8). Best overall response and disease control rates were similar to HM salvage regimens (28 and 64%, respectively). Through multivariate analysis of independent prognostic factors, we designed and prospectively validated a simple prognostic score based on histological subtype, performance status, and albumin. Patients with a low-risk score experienced significantly better OS compared with patients with an intermediate or a high score (median OS: 37 vs. 17 vs. 5 months; hazard ratio=11.68, 95% CI: 4.09–33.3). Our data indicate the safety and efficacy of phase I trials in a significant number of relapsed/refractory HM patients, with clinical benefit achieved in more than half of patients. Our simple scoring system offers a valuable selection tool encouraging HM patient inclusions in phase I trials.