Rationale: Wnt/β-catenin signaling has been implicated in lung fibrosis, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. Objectives and Methods: We examined mice with impaired Wnt signaling due to loss of the Wnt co-receptor Lrp5 in models of lung fibrosis induced by bleomycin or an adenovirus encoding an active form of TGF-β. We also analyzed gene expression in peripheral blood mononuclear cells (PBMC) from patients with idiopathic pulmonary fibrosis (IPF). Measurements and Main Results: In patients with IPF, analysis of PBMC revealed that elevation of positive regulators, LRP5 and 6 were independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of IPF patients. Lrp5 null mice were protected against bleomycin-induced pulmonary fibrosis, an effect that was phenocopied by direct inhibition of β-catenin signaling by the small molecular inhibitor, iCRT3. Transplantation of Lrp5 null bone marrow cells into wild-type mice did not limit fibrosis. Instead, Lrp5 loss was associated with reduced TGF-β production by alveolar type 2 cells and leukocytes. Consistent with a role of Lrp5 in the activation of TGF-β, Lrp5 null mice were not protected against lung fibrosis induced by TGF-β. Conclusions: We show that the Wnt co-receptor, Lrp5, is a genetic driver of lung fibrosis in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGFβ signaling can override a loss in Lrp5 has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis.