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Objectives: To identify the immunohistochemical pattern of non‐tumoral epithelium adjacent to lip cancer (ANTE) to unveil molecular alterations and potential biomarkers in lip cancer patients. Materials and Methods: A systematic search at MEDLINE, EMBASE and proceedings Web of Science, OpenGrey and WorldCat. The PICOS outline (Population: lip cancer patients; Intervention: immunostaining with biomarkers in surgical specimens; Comparisons: ANTE versus LC; Outcomes: primary—to identify the immunohistochemical pattern of peritumoral epithelium and secondary—to assess the immunoreactivity of LC epithelium; and Study design: cross‐sectional, case‐control and cohort studies). Results: A total of 339 records were identified. Seven studies reporting on ANTE and LCs were included in the qualitative synthesis, and 4 of them (p53 immunostaining) were selected for meta‐analysis. In the ANTE group, the pooled prevalence of p53 was 0.74 (95% CI: 0.66 – 0.82), while in the lip squamous cell carcinoma group this prevalence was 0.83 (95% CI: 0.75 – 0.89). Conclusions: Similar immunoexpression was found in lip epithelium adjacent to lip carcinoma, even in epithelia with normal appearance or mild histological alterations. The role of biomarkers in the follow‐up of actinic cheilitis patients deserves additional clinical assessment. [ABSTRACT FROM AUTHOR]