Methylation of p16 gene is a relatively frequent molecular finding in multiple myeloma (MM), but its clinical implication is disputable. Cell cycle regulators are now recognized as active in the control of angiogenesis, which is an integral component of pathogenesis and a target for new treatment modalities of this disease. On such background, we focused on determining whether loss of p16 function by methylation could be associated with increased angiogenesis and VEGF expression, and the prognostic relevance of p16 methylation in 50 untreated, newly diagnosed MM patients. Thirty-one percent (13/42) of 42 patients assessable for p16 gene methylation showed to be methylation-positive. High-angiogenesis was present in 73% of cases, but methylation of the p16 gene did not associate with angiogenesis or with VEGF expression. Also, p16 methylation did not show prognostic relevance or correlation with the clinical and laboratory parameters of prognostic significance in univariate analysis. P16 immunoexpression presented only a faint agreement with the molecular study. Therefore, p16 methylation seems to have no correlation with angiogenesis and VEGF expression, neither with overall and event-free survival in MM patients. Besides, P16 immunohistochemistry seems inadequate to substitute the molecular study of methylation in this type of tumor cells. Additional studies are needed to clarify the correspondence between the epigenetic alteration of the p16 gene and its protein immunexpression, and the clinical relevance of p16 methylation in MM patients.