Melanoma is a highly metastatic cancer, and its incidence has increased over the past several decades. Angiogenesis is associated with melanoma metastasis and a poor prognosis. Many genetic and epigenetic factors affecting tumour vascularization and metastasis have been investigated, despite the heterogeneity of cancer cells and the complicated mechanisms involved in melanoma. Nemo-like kinase (NLK) is a serine/threonine kinase regulating the transcription factor by negatively regulating Wnt and downstream vascular endothelial growth factor receptor 2 (VEGFR2) signalling. This study aimed to investigate whether NLK expression in melanoma correlates with VEGFR2-related angiogenesis and melanoma metastasis. Immunohistochemistry analysis using 175 biopsied tissues of melanoma patients showed that NLK is expressed in 72.6% of melanoma tissues, whereas 27.4% of the samples showed absent expression of NLK. In metastatic melanoma, the expression of NLK was significantly lower than that in primary melanoma (P=0.002). Furthermore, tissues with a lower expression of NLK showed a higher microvessel density as detected by VEGFR2 expression compared with tissues showing higher NLK expression. These data suggest that reduced expression of NLK in melanoma correlates with VEGFR2-related microvessel formation and melanoma metastasis. This study showed that NLK may serve as a novel prognosis marker and revealed new mechanisms in melanoma metastasis.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.