The CDKN2b–CDKN2a locus on chromosome 9p21 in human (chromosome 4 in mouse) is frequently lost in cancer. The locus encodes three cell cycle inhibitory proteins: p15^INK4b encoded by CDKN2b, p16^INK4a encoded by CDKN2a and p14^ARF (p19^Arf in mice) encoded by an alternative reading frame of CDKN2a (ref. ). Whereas the tumour suppressor functions for p16^INK4a and p14^ARF have been firmly established, the role of p15^INK4b remains ambiguous. However, many 9p21 deletions also remove CDKN2b, so we hypothesized a synergistic effect of the combined deficiency for p15^INK4b, p14^ARF and p16^INK4a. Here we report that mice deficient for all three open reading frames (Cdkn2ab^-/-) are more tumour-prone and develop a wider spectrum of tumours than Cdkn2a mutant mice, with a preponderance of skin tumours and soft tissue sarcomas (for example, mesothelioma) frequently composed of mixed cell types and often showing biphasic differentiation. Cdkn2ab^-/- mouse embryonic fibroblasts (MEFs) are substantially more sensitive to oncogenic transformation than Cdkn2a mutant MEFs. Under conditions of stress, p15^Ink4b protein levels are significantly elevated in MEFs deficient for p16^Ink4a. Our data indicate that p15^Ink4b can fulfil a critical backup function for p16^Ink4a and provide an explanation for the frequent loss of the complete CDKN2b–CDKN2a locus in human tumours.