BACKGROUND: Perineural invasion (PNI) in cutaneous squamous cell carcinoma (CSCC) may portend a poor prognosis for patients. p75NGFR (nerve growth factor receptor) is part of a membrane receptor complex that binds nerve growth factor. Its use for detecting PNI in CSCC in comparison with S-100 immunohistochemical staining has not been explored. OBJECTIVE: To determine whether detection of PNI may be improved by staining with p75NGFR compared with hematoxylin and eosin (H&E) and S-100. METHODS: Thirty-four cases of CSCC were retrospectively evaluated for the presence of PNI using standard H&E, as well as S-100 and p75NGFR immunohistochemical stains. Staining intensity was correlated to the presence or absence of PNI and tumor differentiation. RESULTS: The results showed a positive correlation between staining intensity and the presence of PNI detected by p75NGFR (p=.04). Using p75NGFR allowed for the detection of seven cases of PNI not detected by H&E alone. Five of these cases were detected by S-100, with two cases seen by p75NGFR only. Six cases of PNI were detected using S-100 not seen on H&E, with one case also not seen using p75NGFR. CONCLUSION: p75NGFR immunostaining increased detection of PNI compared with H&E. p75NGFR could serve as an alternative to S-100 in the detection of PNI or as part of an immunostaining panel for PNI detection.