Controversy continues to surround the role of p16INK4a in cell cycle control and carcinogenesis. Mutations, deletions and changes in methylation patterns of p16INK4a have been proposed as mechanisms leading to abnormal expression of the gene. We show here that primary and metastatic breast carcinomas demonstrate hypomethylation of p16INK4a which is associated with expression of p16INK4a mRNA, as compared to normal breast tissue which demonstrates a relative hypermethylation of p16INK4a associated with the absence of p16INK4a expression. These data suggest that methylation and lack of expression of p16INK4a is not a central mechanism in the development of breast carcinoma, but rather that the gene is functioning and expressed in breast carcinoma more frequently than in normal breast tissue. The role of p16INK4a is much more complex than has been previously hypothesized.