A proteomic approach to study cardiovascular disease includes the examination of proteins associated with risk factors such as left ventricular hypertrophy (LVH). PrPC is a host-coded membrane-bound glycoprotein found in most cell types, including myocardium, and whose physiological function is uncertain. We have taken a selective proteomic approach and performed mechanistic studies to determine whether PrPC levels are related to left ventricular (LV) structure or function. Echocardiograms were performed at baseline in 65 mice comprising three strains of the same C57Bl/6J x 129SV genetic background but expressing different levels of PrPC (wild-type mice (WT), PrP-/-, and PrPC over-expressing transgenic mice (tga20)). There were no significant differences in LV mass or LV ejection fraction between the three groups. Either normal saline (n = 60) or isoproterenol (n = 55) was then administered intraperitoneally (50 mg/kg/day) for 5 days/wk for two consecutive weeks to induce LVH. Body weight decreased significantly in the PrP-/- group (18%). On multivariate analysis, higher LV mass index posttreatment was independently associated with the tga20 group (versus PrP-/- versus WT, p = 0.002) after adjusting for treatment (isoproterenol versus saline), and weight change (r2 = 0.13 for model, p = 0.016). Therefore, PrPC appears unrelated to LV mass and function in the basal state. Isoproterenol causes transient enhancement of PrPC expression in WT mice and a more pronounced increase in tga20 mice at 2 h posttreatment. Overexpression of PrPC in the tga20 group may be associated with higher LV mass after a 2 wk regimen of isoproterenol.