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Simple Summary: While anti-PD1 antibodies have demonstrated efficacy in some patients with metastatic anal cancer, these agents have no proven benefit for those with localized disease treated with chemoradiation. Difficulty procuring fresh tumor tissue required for RNA and protein expression analysis has limited extensive molecular profiling for this rare cancer. Our team utilized a novel digital spatial profiling technology on pretreatment anal cancer specimens to identify biomarkers associated with recurrence after chemoradiation. We observed that recurrent tumors had higher baseline expression of immune checkpoint biomarkers, higher MAPK signaling activation and higher PI3K/Akt signaling activation. These findings provide a rationale that supports future clinical trials with immunotherapy that seek to improve survival beyond chemoradiation for patients with localized squamous cell cancer of the anus. The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA. [ABSTRACT FROM AUTHOR]