Although much progress has been made, current treatments of peripheral nerve damage mostly result in only partial recovery. Local production of neurite outgrowth-promoting molecules, such as neurotrophins and/or cell adhesion molecules, at the site of damage may be used as a new means to promote the regeneration process. We have now explored the ability of an adenoviral vector encoding the reporter gene LacZ (Ad-LacZ) to direct the expression of a foreign gene to Schwann cells of intact and crushed rat sciatic nerves. Infusion of 8 x 10(7) PFU Ad-LacZ in the intact sciatic nerve resulted in the transduction of many Schwann cells with high levels of transgene expression lasting at least up to 12 days following viral vector administration. The efficacy of adenoviral vector delivery to a crushed nerve was investigated using three strategies. Injection of the adenoviral vector at the time of, or immediately after, a crush resulted in the transduction of only a few Schwann cells. Administration of the adenoviral vector the day after the crush resulted in the transduction of a similar number of Schwann cells 5 days after administration, as observed in uncrushed nerves. Regenerating nerve fibers were closely associated with beta-galactosidase-positive Schwann cells, indicating that the capacity of transduced Schwann cells to guide regenerating fibers was not altered. These results imply that the expression of growth-promoting proteins through adenoviral vector-mediated gene transfer may be a realistic option to promote peripheral nerve regeneration.