The characterization of factors involved in the etiology of melanoma may lead to the identification of new targets for therapy and prognostic markers. Recent data indicate that Nodal can be expressed by malignant melanoma cells and this expression seems to contribute to melanoma development and progression. The aim of this study was to investigate the potential of Nodal as a prognostic marker for stage III/IV patients and as a treatment target for melanoma immunotherapy. We analyzed, by means of immunohistochemistry, 63 patients with stage III/IV melanoma for expression of Nodal in their tumors taken during the course of their disease. Furthermore, to research potential safety issues when immunotherapeutically targeting Nodal, we assessed Nodal expression in normal human adult tissues. We found that Nodal can be expressed at all stages of melanoma progression and there is no significant increase in the frequency of Nodal expression in distant metastases. Furthermore, our data show that there is no correlation between the expression of Nodal during course of disease and survival of patients. Finally, when screening for Nodal expression in normal adult organ tissues, we found consistent expression in renal tissue. We conclude that Nodal expression cannot be used as a prognostic marker for survival of patients with stage III/IV melanoma and as this putative target is renally expressed, it is not well-suited for immunotherapeutic approaches. This study suggests that, despite strong previous suggestions, the role of Nodal in melanoma progression may be less prominent and immunotherapeutic targeting of Nodal could be potentially harmful.