Around 80% of patients who develop acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 infection experience persistent lung dysfunction. The molecular factors that mediate pulmonary sequelae and recovery are unknown. In this context, we sought to comprehensively characterize the proteomic determinants of pulmonary diffusion impairment. This was a prospective cohort study including eighty-seven SARS-CoV-2–induced ARDS survivors. A complete pulmonary function evaluation and chest computed tomography (CT) were performed 3 months after hospital discharge. Proteomic profiling (364 proteins) was performed in plasma samples using proximity extension assay (PEA) technology. Partial least squares-discriminant analysis (PLS-DA) and random forest (RF) methods were used to assess predictor importance. Thirty percent of patients presented moderate to severe impairment of lung diffusing capacity (DLCO<60% predicted). In the univariate analysis, fifteen proteins showed high concentrations in patients with DLCO<60% [false discovery rate (FDR)<0.05]. Pleiotrophin (PTN) displayed the highest differences: fold change=2.22 and FDR=0.001. Differentially detected proteins showed an inverse and independent dose–response relationship with DLCO. The multivariable approaches clustered proteins according to the severity of diffusion impairment. Clusters were composed of host mediators of cell proliferation and differentiation, tissue remodeling, angiogenesis, coagulation, inflammation, immune response and fibrosis signaling. In survivors of SARS-CoV-2–induced ARDS, lung diffusion impairment is associated with specific circulating factors implicated in multiple injury and repair mechanisms. The host protein signatures allow a better understanding of pulmonary sequelae and may constitute therapeutic targets and biomarkers. The long-term biological and clinical significance of these observations requires further investigation.