p16 INK4a is a tumor suppressor protein involved in the pathogenesis of a variety of malignancies and is a 16.5 kDa protein expressed in the nucleoplasm of proliferating cells, functioning as an inhibitor of CDK4. Recent analyses of the p16INK4a gene revealed homozygous deletions, nonsense, missense, or frameshift mutations in several human cancers. p16 INK4a gene has been reported among melanomas, gliomas, esophageal, pancreatic, lung, and urinary bladder carcinomas (1,2). PRAME (preferentially expressed antigen in melanoma) is located on chromosome 22q11.22 and encodes a 509 amino acid protein. PRAME is an autosomal cancer-testis antigen (CTA) gene. PRAME is not only expressed in melanoma, but also various nonmelanocytic malignant neoplasms, including non-small cell lung cancer, breast carcinoma, renal cell carcinoma, ovarian carcinoma, leukemia, synovial sarcoma, and myxoid liposarcoma. Normal healthy tissues are not known to express PRAME except for testis, ovary, placenta, adrenals, and endometrium (3,4). An optimized antibody cocktail for p16 INK4a + PRAME may aid in the clear distinction between nodal nevi from nodal metastatic melanoma. p16 will be expressed in metastatic melanoma; while PRAME will be expressed in non-metastatic melanoma, and the two should not coexpress (5,6).