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Although immune therapies with checkpoint inhibitors have gained increasing attention in advanced and metastatic melanoma, interferon-α remains a standard therapy for nonmetastatic malignant melanoma with risk factors. Interferons can successfully prevent relapse; however, the response rate is still not as high as would be desired. Prognostic tools to predict the response are required, which could lead to more individualized treatment regimens. In numerous studies over the past decade, circulating epithelial tumor cells (CETCs) have been shown to be a promising biomarker for estimating the risk of metastatic relapse, and we sought to determine whether they can also be used for this purpose in malignant melanoma. To establish a prognostic tool for patients with melanoma, we quantified CETCs over the course of interferon treatment in 49 patients. Patients were categorized into two groups according to the behavior of their circulating tumor cells during the interferon treatment: those with increasing and those with decreasing numbers of circulating tumor cells. Patients with increasing numbers of circulating tumor cells had a significantly higher risk of relapse. Kaplan–Meier survival analysis showed a significant difference between patients with increasing CETC numbers (mean survival time: 2.6 years) and patients with decreasing or stable CETC numbers (mean survival time: 12.6 years) (P=0.001). Quantification of CETCs could prove to be a prognostic marker for patients with melanoma receiving interferon immunotherapy. Further studies should determine whether these results are applicable to other immunotherapies, for example, immune checkpoint inhibition.