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Background: Squamous cell carcinoma of the lip accounts for 20% of all oral carcinomas. Its diagnosis may be challenging because it clinically resembles actinic cheilitis and inflammatory lesions of the lips., Objectives: To determine clinical and dermatoscopic predictors of squamous cell carcinoma of the lip vs. other lip lesions., Methods: Multicentre retrospective morphological study, including histologically confirmed cases of squamous cell carcinoma of the lip and controls consisting of actinic cheilitis and inflammatory lesions of the lips. Clinical and dermatoscopic images were evaluated for the presence of predefined criteria. Crude and adjusted odds ratios and corresponding 95% confidence intervals were calculated by univariate and multivariate logistic regression respectively., Results: A total of 177 lip lesions were evaluated, 107 (60.5%) were squamous cell carcinomas and 70 (39.5%) were controls. The most frequent dermatoscopic criteria of lip squamous cell carcinoma were scales (100%), white halos (87.3%) and ulceration (79.4%). The majority of squamous cell carcinomas displayed polymorphic vessels (60.8%), with linear (68.6%) and hairpin (67.6%) being the most frequent types. Multivariate logistic regression analysis showed that clinical predictors of lip squamous cell carcinoma were exophytic appearance and clinical hyperkeratosis, with 43-fold and 6-fold higher probability respectively. White clods and ulceration in dermoscopy presented a 6-fold and 4-fold increased risk for squamous cell carcinoma respectively., Conclusions: A scaly lesion with exophytic growth, dermatoscopically displaying white clods, ulceration and linear and hairpin vessels is very likely a squamous cell carcinoma of the lip., (© 2021 European Academy of Dermatology and Venereology.)