The interleukin-6 signal transducer gp130 is involved in inflammation and pain. Here, we have investigated the role of gp130 in the regeneration of peripheral sensory neurons using conditional knock-out mice (SNS-gp130^-/-; Andratsch et al., J. Neurosci, 2009). Dorsal root ganglion (DRG) cultures from SNS-gp130^-/- mice showed significantly reduced neurite extension and less neurite bearing neurons as compared to controls. Furthermore, the addition of neurotrophins like NGF or BDNF did not rescue neurite outgrowth in SNS-gp130^-/- cultures. However, preliminary evidence suggests that adenoviral re-expression of gp130 in cultured gp130 deficient neurons restored neurite extension. Mechanical and heat sensitivity and motor capabilities were monitored for 25 days after sciatic nerve crush injury in vivo. Recovery of sensitivity was similar in wild type and gp130^fl/fl control mice but significantly delayed in SNS-gp130^-/- mice. To elucidate potential signaling partners in gp130-dependent regeneration we used Affymetrix® gene chip expression analysis of mRNA harvested from DRG explants. We found down-regulation of two regeneration-associated genes (RAG), Atf3 and Sprr1a, in SNS-gp130^-/- DRG explants and this was confirmed by quantitative PCR. mRNA of both Atf3 and Sprr1A was lower in non-injured SNS-gp130^-/- compared to gp130^fl/fl DRG but increased after sciatic nerve injury at 3 and 7 days in both mice strains suggesting that Atf3 and Sprr1a may not be essential for regeneration in peripheral neurons. Our data show that regeneration of neurons was significantly impaired in SNS-gp130^-/-in vitro and in vivo. We therefore suggest that gp130 is an important regulator of regeneration in peripheral neurons. Supported by FWF (P18444) and DK SPIN