Despite the great heterogeneity in the previously reported results on the prognostic significance of p16Ink4A in lung malignancies, our analyses demonstrate that p16Ink4A status, if assessed using an accurate semi-quantitative system at the immunohistochemical level, is an independent prognostic factor in lung tumors, being related to poorer prognosis in neuroendocrine entities, and to a more favorable outcome in non-neuroendocrine malignancies. This evidence concerns the gene CDKN2A and lung neoplasm.