The transition from stable to rupture-prone and ruptured atherosclerotic plaques involves many processes, including an altered balance between inflammation and fibrosis. An important mediator of both is transforming growth factor (TGF)-β, and a pivotal role for TGF-β in atherogenesis has been postulated. Here, we determine the in vivo effects of TGF-β inhibition on plaque progression and phenotype in atherosclerosis. Recombinant soluble TGF-β receptor II (TGFβRII:Fc), which inhibits TGF-β signaling, was injected in apolipoprotein E-deficient mice for 12 weeks (50 μg, twice a week intraperitoneally) as early treatment (treatment age 5 to 17 weeks) and delayed treatment (age 17 to 29 weeks). In the early treatment group, inhibition of TGF-β signaling treatment resulted in a prominent increase in CD3- and CD45-positive cells in atherosclerotic lesions. Most profound effects were found in the delayed treatment group. Plaque area decreased 37.5% after TGFβRII:Fc treatment. Moreover, plaque morphology changed into an inflammatory phenotype that was low in fibrosis: lipid cores were 64.6% larger, and inflammatory cell content had increased 2.7-fold. The amount of fibrosis decreased 49.6%, and intraplaque hemorrhages and iron and fibrin deposition were observed frequently. TGFβRII:Fc treatment did not result in systemic effects. These results reveal a pivotal role for TGF-β in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques.