Melanoma cell lines and melanoma tumours express glutamate receptors, including the N-methyl-D-aspartate (NMDA) receptor. Previous exome sequencing studies demonstrated that up to a third of human melanoma samples carry mutations in the GRIN2A gene. GRIN2A encodes the regulatory GluN2A subunit of the NMDA receptor. The NMDA receptor is best known for its neurotransmitter functions but has also been shown to promote cell survival and invasion in other cell types, which may be of relevance in the context of cancer. Here, GRIN2A mutations were studied in low-passage melanoma cell lines derived from patients with metastatic melanoma and clinical correlations were sought. NMDA receptor expression characteristics were also thoroughly examined in these lines. We found that melanoma cell lines expressed transcripts for several NMDA receptor subunits and carried mutations within evolutionarily conserved domains of GRIN2A. Five non-synonymous mutations in GRIN2A were detected in four of 19 melanoma cell lines (21%). Mutations were located within conserved domains of GluN2A and were computationally predicted to be ‘disease-causing’. Molecular modelling of the Gly762Glu mutation within the crystal structure of GluN2A-GluN1 heterodimer demonstrated conformational changes in the hinge region of the glutamate-binding ‘clam-shell’ region and at the interface with GluN1. The presence of GRIN2A mutations correlated with poor patient outcome, which was in contrast to the BRAF V600E mutation (consistent with the fact that none of these patients received BRAF inhibitors). Our study provides the first indication that the presence of GRIN2A mutations is associated with poor patient outcome, highlighting the contribution of the NMDA receptors to melanoma biology. Further work will examine how NMDA receptor modulation affects survival and invasion of melanoma cells in vitro.