<b><i>Background:</i></b> Subungual melanoma (SM) is an unusual type of melanocytic tumor affecting the nail apparatus. The mutational prevalence of the most prominently mutated genes in melanoma has been reported in small cohorts of SM, with unclear conclusions on whether SM is different from the rest of melanomas arising in acral locations or not. Hence, the molecular profile of a large series of SM is yet to be described. <b><i>Objectives:</i></b> The aim of this study was to describe the molecular characteristics of a large series of SM and their association with demographic and histopathological features. <b><i>Methods:</i></b> Patients diagnosed with SM between 2001 and 2021 were identified from six Spanish and Italian healthcare centers. The mutational status for <i>BRAF, NRAS, KIT,</i> and the promoter region of <i>TERT (TERTp)</i> were determined either by Sanger sequencing or next-generation sequencing. Clinical data were retrieved from the hospital databases to elucidate potential associations. <b><i>Results:</i></b> A total of 68 SM cases were included. Mutations were most common in <i>BRAF</i> (10.3%) and <i>KIT</i> (10%), followed by <i>NRAS</i> (7.6%), and <i>TERT</i>p (3.8%). Their prevalence was similar to that of non-subungual acral melanoma but higher in SM located on the hand than on the foot. <b><i>Conclusions:</i></b> To date, this study represents the largest cohort of SM patients with data on the known driver gene mutations. The low mutation rate supports a different etiopathogenic mechanism for SM in comparison of non-acral cutaneous melanoma, particularly for SM of the foot.