Technical Abstract: Changes in dietary selenium and selenoprotein status may influence both anti- and pro-cancer pathways, making the outcome of interventions different from one study to another. To characterize such outcomes in a defined setting, we undertook a controlled hepatocarcinogenesis study involving varying levels of dietary selenium and altered selenoprotein status using mice carrying a mutant (A37G) selenocysteine tRNA transgene (TrsptG37) and/or TGFa. The use of TrsptG37 allowed us to alter selenoprotein expression in a selenoprotein and tissue specific manner and, at sufficient dietary selenium, separate the effect of diet and selenoprotein status, whereas TGFa was employed as the driver of hepatocarcinogenesis. We subjected these mice to diets deficient in selenium (0.02 ppm selenium) or supplemented with 0.1, 0.4 or 2.25 ppm selenium as selenite or 30 ppm triphenylselenonium chloride (TPSC), a non-metabolized selenium compound. TrsptG37 transgenic and TGFa/TrsptG37 bi-transgenic mice maintained on selenium-deficient or TPSC diets developed early morbidity and mortality prior to tumor formation, and showed a characteristic neurologically lethal phenotype. Pathological analyses revealed widespread disseminated pyogranulomatous inflammation, wherein pyrogranulomas occurred in liver, lungs, heart, spleen, small and large intestine, and mesenteric lymph nodes in the TrsptG37 transgenic and TGFa/TrsptG37 bi-transgenic mice fed the selenium-deficient or TPSC diets. The incidence of hepatocarcinogenesis was significantly increased in mice carrying the TGFa transgene; however, neither dietary selenium nor selenium status, separately or in combination, influenced hepatocarcinogenesis in these animal models. Thus, dietary selenium and selenoprotein status do not affect hepatocarcinogenesis driven by TGFa, but their deficiency leads to widespread pyogranuloma formation.