A 10-year-old boy, affected by cleft lip and palate and the Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) syndrome, presented with hypodontia, microdontia, enamel hypoplasia and caries, as well as white macules and plaques on the buccal mucosa bilaterally. Verrucous plaques were noted on the right side and a smooth diffuse white macule was present on the left side. Samples of each were taken by incisional biopsy. Microscopic analysis revealed oral mucosa comprised of hyperplastic stratified squamous epithelium with either hyperparakeratosis or lack of keratinization. There was extensive hydropic degeneration and sparse cells with perinuclear eosinophilic condensation were identified. The underlying fibrous connective tissue exhibited blood vessels with mild subepithelial mononuclear inflammatory infiltrate, bundles of skeletal striated muscle fibers, and areas of hemorrhage at deeper regions. White sponge nevus was diagnosed. To our knowledge, no other case of white sponge nevus has been reported in a patient with EEC syndrome. Considering the low prevalence of this disorder and also of the EEC syndrome, future studies on the etiology of the white sponge nevus might look at the common etiopathogenic aspects of both the white sponge nevus and the EEC syndrome.