Tamoxifen has been found to be neuroprotective in both transient and permanent experimental ischemic stroke. However, it remains unknown whether this agent shows a similar beneficial effect after spinal cord injury (SCI), and what are its underlying mechanisms. In this study, we investigated the efficacy of tamoxifen treatment in attenuating SCI-induced pathology. Blood-spinal cord barrier (BSCB) permeability, tissue edema formation, microglial activation, neuronal cell death and myelin loss were determined in rats subjected to spinal cord contusion. The results showed that tamoxifen, administered at 30 min post-injury, significantly decreased interleukin-1beta (IL-1beta) production induced by microglial activation, alleviated the amount of Evans blue leakage and edema formation. In addition, tamoxifen treatment clearly reduced the number of apoptotic neurons post-SCI. The myelin loss and the increase in production of myelin-associated axonal growth inhibitors were also found to be significantly attenuated at day 3 post-injury. Furthermore, rats treated with tamoxifen scored much higher on the locomotor rating scale after SCI than did vehicle-treated rats, suggesting improved functional outcome after SCI. Together, these results demonstrate that tamoxifen provides neuroprotective effects for treatment of SCI-related pathology and disability, and is therefore a potential neuroprotectant for human spinal cord injury therapy.