Objectives This study examined the effects of long-term monotherapy with rosuvastatin (RSV) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with heart failure (HF). Background 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or “statins” possess other noncholesterol-lowering properties that include inhibiting proinflammatory cytokines, attenuating LV hypertrophy, and stimulating the release of bone marrow-derived stem cells (BMSCs). Methods Twenty-one dogs with microembolization-induced HF were randomized to 3 months oral monotherapy with low-dose (LD) RSV (0.5 mg/kg once daily, n = 7), high-dose (HD) RSV (3.0 mg/kg once daily, n = 7), or to no therapy (control group, n = 7). The change (Δ) from pre- to post-therapy (treatment effect) in LV end-diastolic volume (EDV) and end-systolic volume (ESV) and ejection fraction (EF) was measured. Protein level of tumor necrosis factor (TNF)-α in LV tissue and the number of circulating Sca-1–positive BMSCs was also determined. Blood and LV tissue from 6 normal dogs was obtained and used for comparison. Results There were no differences in ΔEDV, ΔESV, and ΔEF between control group and LD RSV. In contrast, ΔEDV and ΔESV were significantly lower, and ΔEF was significantly higher in HD RSV compared with control group. High-dose, but not LD, RSV also normalized protein levels of TNF-α and was associated with a significant increase in the number of circulating BMSCs. Conclusions In dogs with HF, chronic therapy with HD RSV prevents progressive LV dysfunction and dilation. This benefit may be partly derived from normalization of TNF-α expression and partly from increased mobilization of BMSCs.