(1) Background: Melanoma is the most common life-threatening cancer among skin cancers. Almost all locations of the skin can be affected by melanoma, and the upper limbs are one of the most frequent locations. We aimed to study the epidemiology and survival outcomes of patients with melanoma localized in the upper extremities compared with other sites.

(2) Methods: The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database is considered the most representative of the U.S. population; we extracted melanoma cases diagnosed between 2000 and 2019. Several characteristics, including demographical, pathological, and therapeutic, were recorded, and upper extremity melanomas and melanomas from other areas were compared. Overall survival was assessed, and the groups were compared.

(3) Results: 69,436 patients had melanoma in the upper limbs and shoulders and 204,794 in other body parts. Overall, 35,267 patients with upper extremity melanoma were males, 34,169 were females, and the mean age was 60. For the rest of the body, there were 118,654 males and 86,140 females, with a mean age of 59. Surgery alone was the most commonly used treatment, while radiation therapy was the least used for all sites. Women appear to have better survival than men. Superficial spreading melanoma is the least lethal subtype, while nodular melanoma is the most dangerous.

(4) Conclusion: Women under 50 are more at risk than men of the same age. The trend reverses after age 50 where men are at greater risk. In addition to gender and age, disease stage and major histologic subtypes influence survival.