Squamous cell carcinoma (SCC) of salivary glands, also referred to as epidermoid carcinoma, is a very rare neoplastic tumor. It occurs as metastasis of a cutaneous or mucosal squamous carcinoma of the head and neck or as a primary SCC. In the latter case, the most known risk factor is previous irradiation to the gland. Common clinical symptoms are represented by cervical swelling and hyposialia. The treatment is essentially surgical, most often supplemented by a radical neck dissection and postoperative radiation therapy. A 75-year-old male patient with a history of chronic smoking was consulted for a tumefaction in the right submandibular region evolving for three months. No cervical lymphadenopathy in the submandibular and superior jugulo-carotid areas was palpable. CT scan showed an enhancing heterogeneous process of the right cervical region, invading the mylohyoid and stylohyoid muscles. A biopsy-excision of the lesion has shown a keratinizing tumor with cytonuclear atypia, consistent with SCC. Radical resection of the mass was associated with the removal of the infiltrated skin. The cutaneous defect was repaired with a rhomboid flap. The patient was started on sessions of adjuvant radiotherapy and chemotherapy. Eight months postoperatively, the patient came for follow-up, with no signs of local disease. The EGFR protein is found in ~70% of salivary neoplasms and is considered as a factor of poor prognosis and rapid proliferation. PET CT is currently the best examination to detect the existence of a concomitant malignant lesion. Diagnosis of primary SCC (PSCC) of the submandibular gland is made on histopathology. Differential diagnoses include mucoepidermoid carcinoma, lymphoepithelial carcinoma and submandibular metaplasia. There is an increased prevalence of nodal involvement in the PSCC, which justifies neck dissection (regions I, II and III of the neck). The RAS mutation leading to resistance to anti-EGFR therapies may be assessed. This would allow for a treatment depending on molecular features for metastatic PSCCs. PSCC of major salivary glands is a very rare lesion with local and general aggressiveness. The diagnosis is based on a combination of clinical examination, MRI, fine needle aspiration and histological examination. Immunotherapy constitutes a ground of research to treat metastatic and advanced pathological cases.