The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)alpha 1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFR alpha 1 released by nerves enhances PNI, even in the absence of cancer cell GFR alpha 1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFR alpha 1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFR alpha 1, which potentiates RET activation and cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFR alpha 1(+/-) mice compared with GFR alpha 1(+/+) mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFR alpha 1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFR alpha 1 expression, suggesting an alternate source of GFR alpha 1 in PNI. These findings collectively demonstrate that GFR alpha 1 released by nerves enhances PNI through GDNF-RET signaling and that GFR alpha 1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior.