Rationale: Prostaglandin (PG) E₂, a cyclooxygenase-derived lipid mediator, is a potent down-regulator of fibroblast activation in normal lung fibroblasts. Although fibroblasts from patients with idiopathic pulmonary fibrosis are known to exhibit a defect in PGE₂ synthesis, there is little information about their responsiveness to this lipid mediator. Objective: To compare responses to PGE₂ in normal, usual interstitial pneumonia (UIP), and other diffuse parenchymal lung disease (DPLD) fibroblasts. Methods: Fibroblasts were grown in vitro from well-characterized control (n=7), UIP (n=17), or other DPLD (n=13) lung tissue. The effects of PGE₂ on fibroblast proliferation and collagen expression were determined. Measurements and Main Results: Only 3 of 12 UIP fibroblast lines exhibited PGE₂-mediated inhibition of both collagen synthesis and cell proliferation, as opposed to 6 of 6 non-fibrotic control cell lines. The degree of PGE₂ resistance in DPLD fibroblasts was quite variable, with UIP cells exhibiting the greatest degree of resistance to PGE₂ while other DPLD fibroblasts manifested a degree of resistance intermediate between control and UIP. The resistance to suppression of collagen expression correlated with worse lung function. Molecular mechanisms for resistance included altered E prostanoid receptor profiles and diminished expression of the downstream kinase, protein kinase A. Conclusion: The recognition that UIP fibroblasts manifest variable refractoriness to PGE₂ suppression sheds new light on the activation phenotype of these cells and on the pathogenesis of fibrotic lung disease.