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With worldwide significance, these alkaloids can contaminate or be naturally present in the human food supply. To develop a small animal model that may be used to compare the carcinogenic potential of the various DHPAs, male heterozygous p53 knockout mice were administered a short\u2010term treatment of riddelliine 5, 15 or 45 mg kg<jats:sup>\u20131<\/jats:sup> bodyweight day<jats:sup>\u20131<\/jats:sup> by oral gavage for 14 days, or dosed a long\u2010term treatment of riddelliine 1 mg kg<jats:sup>\u20131<\/jats:sup> bodyweight day<jats:sup>\u20131<\/jats:sup> in pelleted feed for 12 months. Exposure to riddelliine increased the odds of tumor development in a dose\u2010responsive manner (odds ratio 2.05 and Wald 95% confidence limits between 1.2 and 3.4). The most common neoplastic process was hepatic hemangiosarcoma, which is consistent with published lifetime rodent riddelliine carcinogenesis studies. Angiectasis (peliosis hepatis) and other previously unreported lesions were also identified. The results of this research demonstrate the utility of the heterozygous p53 knockout mouse model for further investigation of comparative carcinogenesis of structurally and toxicologically different DHPAs and their <jats:italic>N<\/jats:italic>\u2010oxides. Published 2015. 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