Poliovirus-based vectors (replicons) have been shown to maintain the in vitro tropism of poliovirus for motor neurons of the CNS. To determine if replicons could be effective for delivery of potentially beneficial proteins to the CNS, we have constructed and characterized a replicon encoding IL-10. IL-10 was rapidly produced in tissue culture cells following in vitro infection with replicons encoding IL-10. Intrathecal inoculation of replicons encoding IL-10 into the non-injured CNS of mice transgenic for the poliovirus receptor resulted in expression of IL-10 within motor neurons at 24-48 h post-inoculation, which subsided by 72-96 h post-inoculation. Single intrathecal or intramuscular injections of replicons were given following spinal cord trauma. Animals receiving replicons encoding IL-10 demonstrated a greater functional recovery in the first 24 h after injury that was maintained throughout the testing period. Compared to animals given replicons encoding gfp, CNS tissue from animals given replicons encoding IL-10 revealed extensive expression of IL-10 from astrocytes around the CNS lesion during the first week following injury. The expression of IL-10 from astrocytes also correlated with more resting microglia as opposed to the rounded activated microglia seen in animals given replicons encoding gfp. Results of these studies establish that replicons can be used to express biologically active molecules in motor neurons of the CNS and these biologically active molecules can have a direct effect on the CNS or induce a cascade of molecules that can influence the cellular composition and activation state of cells within the CNS. © 2005 Elsevier Inc. All rights reserved.