Aberrations of chromosome 9 p21-22 are involved in the genesis of many forms of cancer. The gene p16 and p15 have been assigned to this region. Both p16 and p15 are an inhibitor of cyclin D-cdk4,cyclin D-cdk6 complex and have been implicated in a wide variety of cancer types, including the germline of patients with familial melanoma. In order to investigate and compare the status of p16,p15 gene in primary tumors and cell lines, we examined 357 primary tumors and 29 cell lines derived from diverse tumor types. In addition to analysis of these primary tumors and cell lines, blood specimens from 91 patients either with sporadic multiple cancers or from cancer-prone families were also analyzed. The data showed the following: 1) Homozygous deletions of p16,p15 were comparatively rare and far less common than previously reported, although hemizygous deletions were observed in a significant fraction of many tumor types; 2) the incidence of p16,p15 deletions (either homozygous deletions or heterozygous deletions) varied significantly among different tumor types; 3) most deletions involved in both p16 and p15 genes; 4) sequence variations in the coding sequence of p16,p15 were comparatively rare among these tumor types, though mutations and polymorphisms were identified; 5) some tumors which showed LOH at 9p, containing p16 and p15 gene, did not show deletions or point mutations in the p16,p15 gene. 6) In a subset of retinoblastoma and osteosarcoma where no Rb gene mutations were present a significant fraction was found to contain p16,p15 gene deletions.