Rationale: The molecular pathomechanisms underlying IPF are still elusive, but chronic epithelial injury has recently been suggested as key event. Objective: We investigated the possible implication of endoplasmic reticulum (ER) stress-mediated apoptosis in sporadic IPF. Methods: We analyzed peripheral explanted lung tissues from patients with sporadic IPF (n=24), COPD (n=9) and donors (n=12) for expression of major ER stress mediators and apoptosis markers by means of immunoblotting, semiquantitative RT-PCR, immunohistochemistry and TUNEL method. Measurements and Main Results: Compared to COPD and donor lungs, protein-levels of ER stress mediators such as processed p50ATF-6 and ATF-4 (activating transcription factor-6 and -4), and the apoptosis-inductor CHOP (C/EBP-homologous protein), as well transcript-levels of spliced XBP-1 (X-box binding protein-1) were significantly elevated in lung homogenates and type-II alveolar epithelial cells (AECII) of IPF lungs. Pro-apoptotic, oligomeric forms of Bax, which play a key role in ER stress-mediated apoptosis downstream of CHOP induction, as well caspase-3 cleavage, could be detected in IPF lungs. By means of immunohistochemistry, exclusive induction of active ATF-6, ATF-4 and CHOP in AECII was encountered in IPF, but not in COPD or donor lungs. Immunoreactivity was most prominent in the epithelium near dense zones of fibrosis and fibroblast foci, where these ER stress markers co-localized with markers of apoptosis (TUNEL, cleaved caspase-3). Conclusion: We could unravel a severe ER stress-response in the type-II alveolar epithelial cells of patients with sporadic IPF that may underlie the apoptosis of this cell type and development of fibrosis in this disease.