Abstract Previous research investigating the roles of T effector (Teff) and T regulatory (Treg) cells after injury to the CNS has yielded contradictory conclusions, with both protective and destructive functions being ascribed to each of these T cell subpopulations. In this work, we study this dichotomy by examining how regulation of the immune system affects the response to CNS trauma. We show that, in response to CNS injury, Teff and Treg subsets in the CNS-draining deep cervical lymph nodes are activated, and surgical resection of these lymph nodes results in impaired neuronal survival. Depletion of Treg, not surprisingly, induces a robust Teff response in the draining lymph nodes and is associated with impaired neuronal survival. Interestingly, however, injection of exogenous Treg cells, which limits the spontaneous beneficial immune response after CNS injury, also impairs neuronal survival. We found that no Treg accumulate at the site of CNS injury, and that changes in Treg numbers do not alter the amount of infiltration by other immune cells into the site of injury. The phenotype of macrophages at the site, however, is affected: both addition and removal of Treg negatively impact the numbers of macrophages with alternatively activated (tissue-building) phenotype. Our data demonstrate that neuronal survival after CNS injury is impaired when Treg cells are either removed or added. With this exacerbation of neurodegeneration seen with both addition and depletion of Treg, we recommend exercising extreme caution when considering the therapeutic targeting of Treg cells after CNS injury, and possibly in chronic neurodegenerative conditions.