show Abstracthide AbstractCancer progression is driven by local selective environmental pressures, evolving temporally via genetic and epigenetic alterations to metastasize, evade drug resistance, and more. The human DNA cytosine deaminase APOBEC3B (A3B) has been implicated as a significant source of mutations in cancers, fueling tumor progression and evolution. Here we present a novel genetically engineered cancer mouse model, which conditionally expresses the human protein A3B. Mice expressing high levels of this enzyme have no immediate developmental abnormalities, but males are entirely sterile. Additionally, we show that the rate at which mice develop malignancies is accelerated in those expressing A3B, with the majority of mice developing liver or lymphatic tumors before 600 days. Comprehensive analyses of these tumors reveal that APOBEC3B is a major source of mutation in them. However, there is little evidence of other cancer-promoting consequences, such as RNA-editing and copy-number alterations. This novel mouse model establishes A3B as a cancer driver, in which mutations from the enzyme are the primary driver of tumors.