Objective To investigate the short-term effect of recombinant human erythropoietin (EPO) on patients with severe traumatic brain injury. Methods One hundred and fifty-nine patients with severe traumatic brain injury were randomly divided into EPO (n = 79) and control group (n = 80). EPO group was treated with subcutaneous injection of EPO (100 units/kg) on day 1, 3, 6, 9 and 12 following the brain injury. Glasgow outcome scores (GOS) were used to evaluate the outcomes three months after the treatment. Serum neuron specific enolase (NSE) and S-100β protein were measured within the first three months after treatment. Results In the end, 146 patients (75 of the EPO group and 71 of the control group) completed the trial. Three months after the treatment, Good recovery was found in 33.3% of the EPO and 12.6% of the control group patients (p < 0.05). Serum NSE and S-100β protein were decreased gradually in both groups after treatment, but their levels in the EPO group were lower than that of control group (p < 0.05). There was no statistically significant difference in blood pressure, hemoglobin levels, pneumonia, sepsis or thromboembolic events between the two groups three months after the treatment (p > 0.05). Conclusion Treatment with five doses of recombinant human erythropoietin is associated with an improved functional recovery in patients with severe traumatic brain injury. This treatment does not seem to increase the risk of thromboembolic events or severe infections.