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Background: Photobiomodulation therapy (PBMT) is an effective method for the prevention of oral mucositis. However, the effects of PBMT on oral squamous cell carcinoma (OSCC) have not yet been fully elucidated. This study aimed to evaluate the impact of PBMT in an OSCC‐patient‐derived xenograft (OSCC‐PDX) model. Methods: BALB/c nude mice with OSCC‐PDX models were divided into Control, without PBMT (n = 8); Immediate irradiation, PBMT since one week after tumor implantation (n = 6); and Late irradiation, PBMT after tumors reached 200 mm3 (n = 6). OSCC‐PDX were daily irradiated (660 nm; 100 mW; 6 J/cm2; 0,2 J/point) for 12 weeks. The tumors were collected and submitted to volumetric, histological, immunohistochemistry, and cell cycle analysis. Results: No significant differences in the volumetric measurements (p = 0.89) and in the histopathological grade (p > 0.05) were detected between the groups. The immunohistochemical analysis of Ki‐67 (p = 0.9661); H3K9ac (p = 0.3794); and BMI1 (p = 0.5182), and the evaluation of the cell cycle phases (p > 0.05) by flow cytometry also did not demonstrate significant differences between the irradiated and non‐irradiated groups. Conclusion: In this study, PBMT did not impact the behavior of OSCC‐PDX models. This is an important preclinical outcome regarding safety concerns of the use of PBMT in cancer patients. [ABSTRACT FROM AUTHOR]