The tumor suppressor TP53 is mutated in approximately 70% of Li-Fraumeni syndrome (LFS) families; however, other genes may lead to the predisposition to tumors in other families. We developed a mouse model to search for other tumor suppressors that may be involved in the syndrome. Inbred CE/J mice, which succumb to multiple types of tumors similar to those found in LFS, were crossed with the Trp53-null 129-Trp53tm1Tyj mouse. We monitored the tumor onset and type and found a significant earlier tumor onset in the CE/J:129-Trp53tm1Tyj mice compared with 129-Trp53tm1Tyj mice with a Trp53-null allele. Additionally, in CE/J:129-Trp53tm1Tyj-Trp53+/- mice, the tumors metastasize, which does not occur in other strains of mice. Using simple-sequence length polymorphism analysis for loss of heterozygosity in tumors, we identified a putative tumor suppressor locus within 1 cM on mouse chromosome 11, which encompasses 12 mapped genes.