Poorly differentiated, cytologically malignant, spindle cell neoplasms of the skin may present a diagnostic challenge with important clinical consequences. In particular, the distinction between poorly differentiated cutaneous spindle cell squamous cell carcinoma (SpSCC) and atypical fibroxanthoma (AFX) remains controversial, but with important clinical implications: SpSCC exhibits an increased tendency for both local recurrence and metastasis compared with AFX. AFX is generally accepted as a diagnosis of exclusion based on negativity for a broad panel of immunohistochemical markers, including multiple cytokeratins, melanocytic markers, muscle markers, and vascular markers. As cytokeratins can also be occasionally lost in SpSCC, it would be of tremendous diagnostic value if there were additional specific markers to facilitate the distinction of lineage in this differential diagnostic context. Initial studies demonstrated p63 to be of utility in distinguishing AFX from SpSCC; however, p63 has proved to lack specificity, as it also exhibits variable reactivity in a subset of AFX. Recent studies have shown p40 immunohistochemistry to be a more specific marker than p63 for the designation of squamous differentiation in carcinomas involving other organ systems. In the current study, we define the utility of p40 immunohistochemistry among common cutaneous spindle cell malignancies, and, specifically, we compare the diagnostic accuracy of p40 and p63 in distinguishing AFX from SpSCC. We show that p40 and p63 exhibit comparable sensitivity, but p40 exhibits superior specificity in the distinction of AFX from SpSCC.