The contribution of PML to tumor suppression was evaluated in a spontaneous mouse cancer model, in which a germ line mutation in the p53 gene (p53R172H) recapitulates a human hotspot mutation common in human sporadic and Li-Fraumeni cancers (p53R175H). In this study, we demonstrated that the complete absence of PML from p53wild type/R172H (p53+/R172H) heterozygous mice, but not mutant homozygous mice, reduced survival and influenced tumor manifestation. Strikingly, these phenomena were most pronounced for male mice, suggesting a gender bias for PML influence. Explicitly, p53+/R172H male mice lacking PML developed soft tissue sarcomas that were associated with reduced survival. In the absence of PML, tumors developed in p53+/R172H mice with elevated p53 levels, associated with enhanced levels of the oncogenic activation associated protein p19Arf. Together, these findings suggest that PML is an important tumor suppressor in a germ line mutant p53 mouse model of human cancer.