An investigation was undertaken to study the neurological changes induced by preparations of long-acting local anaesthetics and their components on cutaneous nerves, following a subcutaneous injection into the backs of guinea pigs. Some of the materials tested caused generalized inflammatory reactions in the skin and subcutaneous tissue but little specific injury to the nerves; others caused greater degrees of nerve injury, with little inflammatory reaction. In other words, the nerve injury was not due simply to inflammation. Two kinds of nerve injury are apparent: (a) edema, and (b) destruction with Wallerian degeneration, with or without edema. The rate of nerve regeneration appears to determine the duration of anaesthesia, only a few fibers being necessary for the return of sensation. The materials which tend to approach the ideal long-acting local anaesthetic are procaine amide, procaine–nembutal combination product, procaine base, and cyclaine.