Peripheral nerve crush induces novel projections from noradrenergic sympathetic neurons to sensory ganglia, and it has been suggested that these projections provide an anatomical substrate for chronic pain syndromes that occur after nerve injury. The present study demonstrates that novel sympathetic projections to sensory neurons are also induced in transgenic mice that overexpress nerve growth factor (NGF) in the skin. Specifically, a large proportion of trigeminal neurons in NGF transgenic mice were innervated by tyrosine hydroxylase (TH)-positive pericellular arborizations that were seen only rarely in controls. Electron microscopic analysis of NGF transgenic mice revealed that trigeminal neurons were surrounded by numerous axonal varicosites containing synaptic specializations. Removal of the superior cervical ganglion abolished TH-immunoreactive arborizations in the ipsilateral trigeminal ganglion confirming that these fibers were sympathetic axons. A two-site enzymelinked immunosorbent assay revealed that transgenic ganglia contained a tenfold increase in NGF peptide compared to controls. However, reverse transcriptase polymerase chain reaction analysis showed no apparent expression of transgene mRNA in sensory ganglia, suggesting that the additional NGF was derived from increased NGF expression in the skin. These results indicate that NGF can induce novel sympathetic projections to sensory neurons in vivo and suggests a model in which increased NGF expression plays a role in the development of sympathetic hyperalgesia after nerve injury. © 1994 Wiley-Liss, Inc.