Background Melanoma is the most aggressive form of skin cancer and the leading cause of death from cutaneous tumors. Several studies have associated alterations in the TERT promoter region (pTERT) with gene overexpression, aggressiveness and poor prognosis of the disease. The aim of this study was to clarify the role of pTERT molecular status in paired samples of primary melanoma and metastasis using tissue and plasma to establish a correlation with disease progression and survival. Methods A total of 88 FFPE tissue samples from 53 patients with advanced melanoma were analyzed. Of these, 35 had paired samples. We also examined cfDNA samples from plasma of 25 patients. pTERT mutational status was analyzed using pyrosequencing and digital droplet PCR (ddPCR). pTERT methylation status was evaluated by methylation-specific PCR (MS-PCR), while TERT mRNA expression levels were measured using reverse transcription quantitative PCR (RT-qPCR). Results and discussion We detected a good correlation between primary tumors and metastases in pTERT mutation and methylation status. We were also able to detect pTERT mutations in plasma samples. Interestingly, the C250T mutation was associated with worse survival and higher TERT mRNA expression, compared to the other most common mutation: C228T. In addition, hyper-methylation of the promoter region seems to be related to the progression of pTERT WT patients. These results suggest that TERT gene alterations plays an important role during tumor progression, with the detection of the C250T mutation in tissue and plasma as a potential biomarker of poor prognosis in patients with advanced melanoma.