The efficacy and feasibility of targeting TGF-β in pulmonary fibrosis and lung vascular remodeling in systemic sclerosis (SSc) have not been well elucidated. In this study, we analyzed how blocking TGF-β signaling affects pulmonary abnormalities in fos-related antigen 2 (Fra-2) transgenic mice, a murine model that manifests three important lung pathological features of SSc: fibrosis, inflammation, and vascular remodeling. To interrupt TGF-β signaling in the Fra-2 transgenic mice, we used a pan-TGF-β blocking antibody, 1D11, and transgenic mice in which TGF-β receptor type 2 (Tgfbr2) is deleted from smooth muscle cells and myofibroblasts (α-SMA-CreER; Tgfbr2flox/flox). Global inhibition of TGF-β by 1D11 did not ameliorate lung fibrosis histologically or biochemically, whereas it resulted in a significant increase in the number of immune cells infiltrating in the lungs. In contrast, 1D11 treatment ameliorated the severity of pulmonary vascular remodeling in Fra-2 transgenic mice. Similarly, genetic deletion of Tgfbr2 from smooth muscle cells resulted in improvement in pulmonary vascular remodeling in the Fra-2 transgenic mice as well as a decrease in the number of Ki67-positive vascular smooth muscle cells, suggesting that TGF-β signaling contributes to the development of pulmonary vascular remodeling by promoting the proliferation of vascular smooth muscle cells. Deletion of Tgfbr2 from α-SMA expressing cells had no effect on fibrosis or inflammation in this model. These results suggest that efforts to target TGF-β in SSc will likely require more precision than simply globally inhibiting TGF-β function.