Background: Perineural invasion (PNInv) is a significant risk factor for metastasis and death in cutaneous squamous cell carcinoma (cSCC). Despite this known association, factors contributing to the presence of PNInv are not well characterized.Aims: To determine risk factors associated with the presence of PNInv using the high-risk cSCC criteria developed by the National Comprehensive Cancer Network (NCCN).Methods: After receiving Institutional Review Board approval for this retrospective review, the presence of NCCN high-risk factors for cSCC were recorded for patients treated at a tertiary referral academic medical center, from January 1, 2010 to March 31, 2012. Stepwise logistic regression was used to identify factors associated with the presence of PNInv.Results: PNInv was present in 34 of 507 cSCCs (6.7%). Moderately or poorly differentiated histology (P < .001, OR 6.6 [95% CI, 3.2-13.7]), acantholytic, adenosquamous, or desmoplastic subtype (P =.01, OR 1.8 [95% CI, 0.8-4.2]), and tumors in areas M (≥10mm) and H ( ≥6mm) (P = .05, OR 5.0 [95% CI, 1.2-21.0]) were significantly associated with the presence of PNInv.Conclusions: This data suggests clinicians should have a higher suspicion and may be able to identify PNInv in high-risk cSCC based on the presence of specific high-risk factors.