The familial atypical multiple mole melanoma (FAMMM) syndrome is caused by a germline mutation of p16. More than 90% of the sporadic pancreatic carcinomas contain genetic alterations that inactivate p16. Patients with the FAMMM syndrome have an increased risk of developing pancreatic cancer. Ductal adenocarcinoma is the most common cancer of the pancreas and the one encountered in patients with FAMMM syndrome. Undifferentiated carcinoma with osteoclastic giant cells, also referred to as UCOCGC of the pancreas, is a rare variant of pancreatic cancer. An UCOCGC of the pancreas associated with FAMMM syndrome is described in this report. Molecular analysis confirmed a germline p16-Leiden deletion in the UCOCGC, accompanied by somatic loss of heterozygosity of the second p16 allele, and absence of p16 protein expression in the neoplastic cells. It is the first case reported and it provides additional evidence that UCOCGC can be considered as a variant of conventional ductal adenocarcinoma of the pancreas.