Primary pure squamous cell carcinoma of the duodenum is a very rare type of duodenal neoplasm and is more likely to be presented as a metastatic tumor. The literature offers little information on this subject and includes very few articles and case reports. Laboratory tests, CT and ultrasound examinations, x-rays and immunohistochemical markers assisted us in making this rare diagnosis of primary squamous cell carcinoma of the duodenum in a 47 year old female patient, who presented with weight loss and melena. The 8 cm duodenal tumor with pancreas invasion was resected by a cephalic duodenopancreatectomy. The pathology examination revealed a primary duodenal squamous cell carcinoma moderately differentiated (G2), invasive in the head of the pancreas, with keratinization, stage II B (pT4N0MxL0V0R0). Positive outcome after surgery was highlighted, no recurrence being registered at the 6 month CT scan follow-up.