Substance P (SP) and calcitonin gene-related peptide CGRP) signaling is required for the post fracture increase in Langerhans cell (LC) numbers. Glabrous hind paw skin was harvested from 3-week post fracture wildtype mice (WT-FX-IPSI), fracture mice lacking SP (Tac1−/−-FX-IPSI and Tac1−/−-FX-CONTRA), and fracture mice lacking the calcitonin gene-related peptide receptor (RAMP1−/−-FX-IPSI and RAMP1−/−-FX-CONTRA), with wildtype no fracture mice (WT-NO FX) serving as controls. Immunohistochemical quantification demonstrated a 206% increase in epidermal LC numbers in the WT-FX-IPSI vs WT-NO FX controls, whereas Tac1−/−-FX-IPSI mice had 68% less LCs than the WT-FX-IPSI mice. Similarly, RAMP1−/−-FX-IPSI mice had 78% less LCs than the WT-FX-IPSI mice. Data were analyzed using a one-way analysis of variance (ANOVA) with Bonferroni correction test for post hoc contrasts, error bars indicate SEM, n = 5-6 per cohort. ***P < 0.001 for vs. Control, ## P < 0.01, and ###P < 0.001 vs. FX-IPSI-WT.