Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in the progression of actinic keratosis to cutaneous squamous cell carcinoma (cSCC) and the progression of localized disease to metastatic disease. Currently, no cSCC biomarkers are able to risk stratify recurrent and metastatic disease (RMD).To determine the prognostic value of INPP5A expression in cSCC RMD.This was a multi-center, single-institutional, retrospective cohort study within the Mayo Clinic Health System using immunohistochemical staining to examine cSCC INPP5A protein expression in primary tumors and RMD. Dermatologists and dermatopathologists were blinded to outcome.Low staining expression (LSE) of INPP5A of RMD was associated with poor overall survival (OS) of 31.0 months vs. 62.0 months for high staining expression (HSE) (p=0.0272). A composite risk score (CRS) (CRS=primary + RMD; with HSE=0 & LSE=1; range 0-2) of 0 was predictive of improved OS compared to a CRS of ≥1 (HR = 0.42, 95%CI: 0.21 to 0.84, p=0.0113).This is a multi-center, but single institution study with a Caucasian population.Loss of INPP5A expression predicts poor OS in RMD of cSCC.