Chronic electrical stimulation and extracellular recording combined with morphological examination of nerves in this study provided a detailed description of the time course and extent of fiber atrophy when the trophic influence of the target was removed by ligation of axotomized nerves and neural activity was replaced by chronic stimulation. The major findings are that decline in amplitude of compound action potentials (CAPs) and fiber diameters is rapid after axotomy and is not reversed or prevented by chronic electrical stimulation, as would be predicted if neural activity played an essential role in maintaining normal fiber caliber. Chronic stimulation had a small short-term sparing effect in the first month after axotomy but was counterproductive over long periods. Comparison of the time course of the decline in CAP amplitude and reduction of fiber diameters with described alterations in mRNA expression of neurofilament protein indicates that the early atrophy is too rapid to be accounted for by reduced synthesis and transport of neurofilaments. It is more likely to result from modification of axonal proteins after axotomy. Replacement of neural activity with stimulation may reduce the initial atrophy but, over longer periods, exacerbates the atrophy, possibly by affecting the synthesis and transport of cytoskeletal proteins. These studies show that the trophic control of nerve fiber size is mediated primarily by functional contacts with peripheral targets and that neural activity plays a relatively small role. Without functional contacts, nerve fibers decline in diameter to stable but lower values. The atrophy was exacerbated by imposing neural activity on the relatively quiescent axotomized neurons.