The present study examined the differences between gastrointestinal melanoma (GM) and skin melanoma (SM). The clinicopathological characteristics, the expression of melanoma stem cell markers nestin, sex determining region Y-box 2 and ATP-binding cassette sub-family B member 5, and the presence of the BRAF mutation were evaluated in 10 cases of GM and 31 cases of SM. Patients with GM had an increased mean age compared with those with SM (76 vs. 68 years). In addition, GMs were significantly more likely than SMs to be amelanotic (50 vs. 7%; P=0.001) and display round cells (70 vs. 23%; P=0.02). The mitosis rate was also significantly higher in GM compared with SM (P<0.05). The incidence of lymph-node metastasis (60 vs. 32%; P<0.05) and distant metastasis (10 vs. 6.5%, P=0.02) was significantly higher in GMs compared with SMs. The expression of stem cell markers did not differ significantly between groups, however, in the SM group advanced-stage disease was associated with a significantly higher expression of nestin than early-stage disease (P<0.05). Immunohistochemically, the expression of BRAFV600E was significantly lower in GMs compared with in SMs (1.0 vs. 3.3; P=0.01). These findings indicate that the identification of these features may aid in the diagnosis of GM and SM, as well as contribute to the development of novel targeted therapies against GM.