The p75^NTR neurotrophin receptor has been implicated in multiple biological and pathological processes. While significant advances have recently been made in understanding the physiologic role of p75^NTR, many details and aspects remain to be determined. This is in part because the two existing knockout mouse models (Exons 3 or 4 deleted, respectively), both display features that defy definitive conclusions. Here we describe the generation of mice that carry a conditional p75^NTR (p75^NTR‐FX) allele made by flanking Exons 4–6, which encode the transmembrane and all cytoplasmic domains, by loxP sites. To validate this novel conditional allele, both neural crest‐specific p75^NTR/Wnt1‐Cre mutants and conventional p75^NTR null mutants were generated. Both mutants displayed abnormal hind limb reflexes, implying that loss of p75^NTR in neural crest‐derived cells causes a peripheral neuropathy similar to that seen in conventional p75^NTR mutants. This novel conditional p75^NTR allele will offer new opportunities to investigate the role of p75^NTR in specific tissues and cells. genesis 49:862–869, 2011. © 2011 Wiley‐Periodicals, Inc.