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A recent study reported that the occurrence of depapillated mucosa surrounding oral tongue squamous cell carcinomas (OTSCC) is associated with perineural invasion (PNI). The present study evaluates the reliability of depapillation as a PNI predictor and how it could affect narrow-band imaging (NBI) performance. This is thus a retrospective study on patients affected by OTSCC submitted to radical surgery. The preoperative endoscopy was evaluated to identify the presence of depapillation. Differences in distribution between depapillation and clinicopathological variables were analyzed. NBI vascular patterns were reported, and the impact of depapillation on those was studied. We enrolled seventy-six patients. After evaluation of the preoperative endoscopies, 40 (53%) patients had peritumoral depapillation, while 59 (78%) had a positive NBI pattern. Depapillation was strongly correlated to PNI, 54% vs. 28% (p = 0.022). Regarding the NBI pattern, there was no particular association with depapillation-associated tumors. The presence of depapillation did not affect the intralesional pattern detected by the NBI, while no NBI-positive pattern was found in the depapillation area. Finally, the NBI-guided resection margins were not affected by depapillation. Peritumoral depapillation is a reliable feature for PNI in OTSCC. NBI margin detection is not impaired by depapillation.