TGF-β1 null mice die by 3 to 4 weeks of age due to a severe autoimmune-mediated multifocal inflammation resulting in multi-organ failure. To assess the therapeutic potential of circulating levels of active TGF-β1, we generated mice with endocrine expression of active TGF-β1 on a TGF-β1 null background (TGF-β1 ^(-/-/TG)) by crossing TGF-β1^(+/−) mice with transgenic mice (TG) that express recombinant TGF-β1 specifically in the liver and secrete it in the blood. The TGF-β1 ^(-/-/TG) mice exhibit a survival profile similar to the TGF-β1 ^(-/-) mice indicating a failure to rescue the lethal phenotype. However, serum TGF-β1 levels in the TGF-β1 ^(-/-/TG) mice were restored to near normal levels with expression in all the tissues, notably in the kidney and spleen. Histopathology showed reduced inflammation in the target tissues, especially in the heart. Interestingly, unlike TGF-β1 ^(-/-) mice, the TGF-β1 ^(-/-/TG) mice have glomerulonephritis in their kidneys similar to the TG mice. Thus, the phenotype of TGF-β1 ^(-/-/TG) animal model indicates the potential role of circulating active-TGF-β1 in reducing inflammation, but its failure to rescue lethality in TGF-β1 null mice indicates a critical autocrine role of TGF-β1.