Neurons of the peripheral nervous system are capable of extensive regeneration following axonal injury. This regenerative response is accompanied by changes in gene expression in axotomized neurons and associated nonneuronal cells. In the sympathetic nervous system, a few of the genes affected by axonal injury have been identified; however, a broad sampling of genes that could reveal additional and unexpected changes in expression has been lacking. We have used DNA microarray technology to study changes in gene expression within 48 h of transecting the postganglionic trunks of the adult rat superior cervical ganglion (SCG). The expression of more than 200 known genes changed in the ganglion, most of these being genes not previously associated with the response to injury. In contrast, only 10 genes changed following transection of the preganglionic cervical sympathetic trunk. Real‐time RT‐PCR analysis verified the upregulation of a number of the axotomy‐induced genes, including activating transcription factor‐3 (ATF‐3), arginase I (arg I), cardiac ankyrin repeat protein, galanin, osteopontin, pituitary adenylate cyclase‐activating polypeptide (PACAP), parathyroid hormone‐related peptide, and UDP‐glucoronosyltransferase. Arg I mRNA and protein were shown to increase within neurons of the axotomized SCG. Furthermore, increases in the levels of putrescine and spermidine, a diamine and polyamine produced downstream of arg I activity, were also detected in the axotomized SCG. Our results identified many candidate genes to be studied in the context of peripheral nerve regeneration. In addition, the data suggest a potential role for putrescine and spermidine, acting downstream of arg I, in the regenerative process. © 2004 Wiley Periodicals, Inc. J Neurobiol 59: 216–235, 2004