Accumulation of the amyloid-β peptide (Aβ) in the brain is crucial for development of Alzheimer's disease. Expression of transforming growth factor-β1 (TGF-β1), an immunosuppressive cytokine, has been correlated in vivo with Aβ accumulation in transgenic mice and recently with Aβ clearance by activated microglia. Here, we demonstrate that TGF-β1 drives the production of Aβ40/42 by astrocytes leading to Aβ production in TGF-β1 transgenic mice. First, TGF-β1 induces the overexpression of the amyloid precursor protein (APP) in astrocytes but not in neurons, involving a highly conserved TGF-β1-responsive element in the 5′-untranslated region (+54/+74) of the APP promoter. Second, we demonstrated an increased release of soluble APP-β which led to TGF-β1-induced Aβ generation in both murine and human astrocytes. These results demonstrate that TGF-β1 potentiates Aβ production in human astrocytes and may enhance the formation of plaques burden in the brain of Alzheimer's disease patients.