Background: This study addressed implications of DNA damage and repair in radiation induced cutaneous melanoma (CM) compared to de novo arising mucosal melanoma (MM). The role of DNA repair was assessed through two DNA repair genes: the human DNA repair genes XRCC3 and RAD5. These genes were selected based on significant homology to the radio-resistant Deinococcus radiodurans RecA (46.8% and 42.9% homology, respectively).Methods: DNA damage in melanoma was assessed and quantified by immunoassay for a marker of DNA damage, 8-hydroxy-2’-deoxyguanosine (8-OHdG). Gene expression analysis was measured by RT-qPCR.Results: In cutaneous melanoma, DNA damage was significantly higher in tumor than adjacent non-malignant tissue (p = 0.001 < 0.05). In contrast, for MM, DNA damage was similar in the non-malignant tissue and tumor (p = 0.965 > 0.05). Alcohol use was correlated with higher DNA damage in the MM (p = 0.036 < 0.05) than in the cutaneous melanoma patients (p = 0.104 > 0.05). The high DNA damage in mucosal tissue was not accompanied by induction of XRCC3 and RAD51 expression, compared to non-malignant tissue adjacent to CM.Conclusions: These observations are consistent with a pre-cancerous condition in MM, one in which repair functions are not induced and DNA damage is allowed to accumulate. Defects in repair functions may increase susceptibility to therapy with DNA damaging agents.