RATIONALE: Analyzing the molecular heterogeneity of different forms of organ fibrosis may reveal common and specific factors and thus identify potential future therapeutic targets. OBJECTIVES: We sought to use proteome-wide profiling of human tissue fibrosis to (1) identify common and specific signatures across endstage interstitial lung disease (ILD) cases, (2) characterize ILD subgroups in an unbiased fashion, and (3) identify common and specific features of lung and skin fibrosis. METHODS: We collected samples of ILD tissue (n=45) and healthy donor controls (n=10), as well as fibrotic skin lesions from localized scleroderma and uninvolved skin (n=6). Samples were profiled by quantitative label-free mass spectrometry, Western blotting, or confocal imaging. MEASUREMENTS AND MAIN RESULTS: We determined the abundance of >7900 proteins and stratified these proteins according to their detergent solubility profiles. Common protein regulations across all ILD cases, as well as distinct ILD subsets, were observed. Proteome comparison of lung and skin fibrosis identified a common upregulation of MZB1, the expression of which identified MZB1+/CD38+/CD138+/CD27+/CD45-/CD20- plasma B cells in fibrotic lung and skin tissue. MZB1 levels correlated positively with tissue IgG, and negatively with diffusing capacity of the lung for carbon monoxide (DLCO). CONCLUSIONS: Despite the presumably high molecular and cellular heterogeneity of ILD, common protein regulations are observed, even across organ boundaries. The surprisingly high prevalence of MZB1+ plasma B cells in tissue fibrosis warrants future investigations regarding the causative role of antibody-mediated autoimmunity in idiopathic cases of organ fibrosis, such as idiopathic pulmonary fibrosis (IPF).