Background: Although vast amount of research has been done on genes related to cancers, it remains unclear whether Mitofusin-2 (MFN2) functions as a tumor suppressor or oncogene in cancer progression. The impact of MFN2 on carcinogenesis is likely to be more complicated than expected, so further research is needed. In this study, we aimed to investigate the effect of MFN2 on the pathogenesis of cutaneous squamous cell carcinoma (cSCC). Objectives: The objective of the study was to evaluate the expression of MFN2 in cSCC tissue and to investigate the influence of MFN2 expression on the biological behavior of cSCC. Methods: MFN2 expression was detected in a cSCC cohort consisting 111 samples of patients with long-term follow-up by immunohistochemistry. The influence of MFN2 on biological behavior of cSCC cells was investigated in vitro. Results: Increased MFN2 abundance was found in 76 (68.5%) of cSCC patients. In multivariate analysis using age, gender, lesion site, MFN2 as cofactors, MFN2 expression was an independent risk factor for recurrence of cSCC with a hazard ratio of 3.47 (95% confidence invterval, 2.31-15.03; P=0.001). The proliferative, migratory, and invasive abilitiesof the cells were 2.1-, 2.8-, and 3.1 fold decreased after MFN2-knockdown than control cells (all P<0.001). Conclusion: MFN2 may act as an oncogene by affecting the development of cSCC and can be used as a biomarker to predict the prognosis of cSCC.