Snake melon (Cucumis melo var. flexuosus) is native to the region from Egypt to Iran; therefore, local genotypes in Egypt may contain genes responsible for tolerance to biotic and abiotic stresses. However, no previous studies were done on the genetic diversity in this crop in Egypt. ISSR markers were used to examine genetic relations among 12 Egyptian snake melon accessions collected from different regions. Of the 10 markers tested, 6 produced 68 amplification products, of which, 23 were polymorphic (33.7% polymorphism). The average polymorphism information content (PIC) value was 0.68 over the 6 primers. Pairwise Jaccord's similarity coefficient ranged from 0.88 to 0.98, indicating a narrow diversity. Cluster analysis distinguished two clusters, one from Cairo, and the second represents the rest of accessions from different regions. It was shown that snake melon genotypes that were genetically close were not necessarily close in geographical distance. On a level of non-coding region using 6 ISSR primers, some differences were found among the Egyptian snake melon accessions, confirming the usefulness of the technique in detecting genetic diversity which may help in future genetic improvement programs in this underestimated crop.