Per- and polyfluoroalkyl substances (PFASs) are endocrine disrupting chemicals and previous studies showed that they could be associated with altered vitamin D levels. Since 1965, a massive environmental contamination by PFASs has occurred in North-eastern Italy. This study compared histopathology and prognosis between melanoma patients exposed (n=194) and unexposed (n=488) to PFAS. All patients were diagnosed and/or treated for melanoma at the Veneto Oncological Institute and the University Hospital of Padua (Italy) in 1998-2014. Patients were stratified according to the area of residency and the classification provided by the regional administration. Presence of mitoses was found in 70.5% of exposed patients and 58.7% of unexposed patients (p=0.005). Median follow-up was 90 months (IQR 59-136). 5-year overall survival was 83.7% in exposed patients and 88.0% in unexposed patients (p=0.20); 5-year disease-specific survival was 88.0% in exposed patients and 90.9% in unexposed patients (p=0.50); 5-year disease-free survival was 83.8% in exposed patients and 87.3% in unexposed patients (p=0.20). Our findings suggested that exposure to PFAS was associated with higher level of mitosis in melanoma patients, which may be related to the vitamin D deficiency induced by PFAS. Further studies are required to investigate this relationship and all effects of PFAS on prognosis.