Preservation of hematopoietic stem and progenitor cell survival is required for recovery from radiation-induced myelosuppression. We recently showed the capacity of a single injection of antiapoptotic cytokines, namely stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination (4F, each factor given intravenously at 50 μg/kg) administered shortly after a 5 Gy gamma total body irradiation to prevent monkeys from myelosuppression. As cytokine efficacy depends on the residual stem cell pool, the aim of the present study was to assess the efficacy of 4F in case of high dose irradiation. Adult monkeys (n=7) were globally and frontally irradiated at 7 Gy gamma using a Co60 source (dose rate 20 cGy/mn). Three animals received 4F 2 hours after irradiation and four control animals were injected with the diluant at the same time. Moreover, one of the treated monkeys was grafted with allogeneic mesenchymal stem cells (MSC) to enhance hematopoietic recovery. Human MSCs were infused directly in humerus simultaneously with 4F injection, allowing cell tracking. Treated monkeys experienced a very short period of thrombocytopenia as compared with untreated animals (platelet [PLT] count < 20 x 109/L: 1 ± 1.7 day versus 27 ± 18 days). Areas under the curve (AUC) of PLTs and red blood cells (RBCs) between days 0 and days 90 were higher in treated animals than in controls. The animal treated with 4F + MSC did not differ from the two 4F monkeys. In contrast with 5 Gy irradiated animals previously studied, both treated and untreated monkeys experienced a prolonged period of neutropenia (neutrophil [ANC] count < 0.5 x 109/L: 12 ± 3 days versus 10.3 ± 7.3) and AUCs of ANC did not significantly differ. This study shows that the 4F treatment, as a single dose regimen, prevents thrombocytopenia in high dose irradiation setting and could act as an emergency treatment for nuclear accident or terrorism victims.