In an attempt to answer questions regarding nerve injection injuries, we injected 11 agents in current use and commonly administered by intramuscular injection into the sciatic nerves of adult Wistar rats. Equal volumes of normal saline were used as control. We harvested the sciatic nerves at various times after injection and examined them by both light and electron microscopy. We performed myelinated nerve fiber counts and constructed histograms. Any impairment of motor function was also noted. We gave injections to 79 animals a total of 158 times; 116 injections were directly into the nerve fascicle (intrafascicular) and 42 were into the epineural tissue (extrafascicular). The results revealed considerable variation in the degree of nerve fiber injury according to the agent injected. Minimal damage resulted from the injection of irondextran. meperidine, and cephalothin, and maximal nerve injury followed the injection of penicillin, diazepam, and chlorpromazine. The site of injection was crucial. Intrafascicular injection was invariably associated with severe nerve injury, but, with few exceptions, extrafascicular injection resulted in minimal damage. The quantity of drug injected was also important in determining the degree of injury. Large, heavily myelinated fibers were more susceptible to injection injury than smaller, thinly myelinated nerve fibers. The effect of the injected drug seemed to be related to injury of the nerve fiber unit—both the axon and the Schwann cell with its myelin sheath. Regeneration in damaged nerves was a constant finding; even the most severely injured nerves, with total axonal degeneration, underwent subsequent regeneration.