Recent studies suggested that the MHC class I expression has an important role on the maintenance of synaptic connections and also on neuronal/glial communication. IFN beta is a cytokine that influences the MHC class I expression. Therefore, the present work studied the effects of IFN beta on astrocyte reactivity and synaptic plasticity in the spinal cord. C57BL/6J adult mice were subjected to unilateral sciatic nerve transection after being treated with 10,000 IU of IFN beta for 1 week. Following axotomy, they were kept under treatment for another week. After that, the animals were sacrificed and the lumbar spinal cords were processed for immunohistochemistry and electron microscopy. Placebo and non-treated axotomized groups were used as controls. The results showed an upregulation of GFAP expression in the lesioned spinal cord segments, especially in the IFN treated group. Interestingly, IFN treated animals, showed a grater MHC class I expression coupled with a decrease of synapthophysin immunoreactivity. The ultrastructure of synapses showed a larger pruning of presynaptic terminals in contact with alpha motoneurons, induced by axotomy plus IFN beta treatment. In vitro, primary cultures of astrocytes were treated during 1 week with IFN (non-treated, 100, 500 and 1,000 IU/ml) and processed for immunohistochemistry (GFAP, ezrin and OX-18). They showed a sharp upregulation of GFAP, mostly when subjected to 500 and 1,000 IU. The present results reinforce the role of MHC class I upregulation on the response to injury, both in vivo and in vitro.