Spinal cord injury (SCI) occurs frequently and is a leading cause of permanent disability in young adults. Many immune inhibitors including tacrolimus (FK506) are shown to be helpful in the regeneration of neural tissue following spinal cord injury. FTY720 belongs to a new class of immunosuppressants. The combination of FTY720 and tacrolimus has been reported to elicit synergistic immunosuppresive effects in rat allograft models without causing critical adverse effects. This study was to determine whether the combination of FTY720 and tacrolimus is superior to FTY720 or tacrolimus alone in the treatment of SCI. Forty-eight rats were subjected to a weight-drop contusion at the tenth thoracic level (a 10-g rod dropped from a height of 25 mm). At 30 min after the operation, they were randomly divided into four groups and received treatment with either FTY720 (0.5 mg/kg), tacrolimus (0.5 mg/kg), FTY720 + tacrolimus (0.5 mg/kg and 0.5 mg/kg respectively) or saline via gavage. Functional recovery was evaluated during 42 days after SCI via open-field test, inclined plane test, footprint analysis, somatosensory evoked potentials (SSEPs), and electron microscopic analysis. Rats from three treatment groups showed significantly better locomotor functional outcomes, higher SSEP amplitude, shorter SSEP latency, and milder pathological changes compared with those of control group. Moreover, rats treated with a combination of FTY720 and tacrolimus demonstrated significantly greater functional recovery by day 14 after SCI than those treated with either FTY720 or tacrolimus alone. These results suggest that the combination of FTY720 and tacrolimus could be a potentially effective therapeutic strategy to treat SCI.