Adverse health outcomes in pulmonary fibrosis are associated with extracellular matrix (ECM) accumulation. Although transforming growth factor-β (TGF-β) has been reported to be an important regulator of fibrosis pathogenesis, TGF-β-independent pathways may also be involved. Here, we investigated responses of putative relatively fibrosis-resistant BALB/c mice to transient pulmonary overexpression of oncostatin M (OSM) using an adenovirus vector encoding OSM (AdOSM) and compared responses with the relatively fibrosis-prone C57Bl/6 strain. Interestingly, BALB/c mice showed similar ECM accumulation and collagen 1A1 and 3A1 mRNA elevation to C57Bl/6 mice 7 days after endotracheal administration of AdOSM. TGF-β1 mRNA levels and pSMAD2 signal were not regulated in either strain in total lung extracts. In contrast to C57Bl/6 mice, BALB/c mice lacked eosinophil, Th2 cytokine, and pro-inflammatory cytokine elevation in the broncholveolar space. OSM overexpression induced STAT3 activation and SMAD1/5/8 signaling suppression in lung from both mice strains, which was associated with a downregulation of BMPR2 and BMP ligands, and increased expression of the BMP antagonist gremlin. Although we also observed STAT3 activation and SMAD1/5/8 signaling suppression in mouse lung fibroblast cultures in vitro upon OSM stimulation, immunohistochemistry analyses indicated that the AdOSM-induced pSMAD1/5/8 signal suppression was primarily localized to the airway epithelium. Other gp130 cytokines including IL-6, LIF, CT-1, but not IL-31, also induced STAT3 activation and SMAD1/5/8 signaling suppression in C10 mouse lung epithelial cells and BEAS 2B bronchial epithelial cells, and we found that pharmacological inhibition of STAT3 activation reversed OSM-induced SMAD1/5/8 signaling suppression in vitro. The results demonstrate that OSM induces ECM accumulation in fibrosis-resistant BALB/c mouse lung in the absence of Th2 inflammation or TGF-β signaling, and highlight a dichotomy of STAT3 activation versus SMAD1 suppression in this process.