Objective: To investigate the relationship between pulmonary fibrosis and endoplasmic reticulum stress (ERS) in rats with paraquat poisoning., Methods: One hundred male Sprague-Dawley (SD) rats were randomly divided into control group (n=10) and paraquat poisoning group (n=90). The animals were sacrificed by exsanguination at 2, 6, 12, 24, 48, 72, 96, 168, 336 hours after administration with 20% parquat solution. The paraffin sections of lung tissue were stained with hematoxylin-eosin (HE) and Masson trichrome to observe the pathological changes. Glucose-regulated protein 78 (GRP78) was determined by immunohistochemistry, and malondialdehyde (MDA) of lung tissue was measured. The total protein of tissue was abstracted, and the α-smooth muscle actin (α-SMA) and GRP78 was detected by Western blotting., Results: HE and Masson staining demonstrated inflammatory infiltration and collagen deposition in the lung after paraquat administration with a tendency of exaggeration with time, and finally resulted in fibrosis. The expressions of MDA, α-SMA and GRP78 in the lung tissue were significantly increased 2 hours after paraquat administration compared with those of control group (MDA: 1.38 ± 0.18 nmol/mg vs. 0.85 ± 0.05 nmol/mg, α-SMA: 0.23 ± 0.01 vs. 0.14 ± 0.03, GRP78: 0.72 ± 0.02 vs. 0.37 ± 0.06, P<0.05 or P<0.01), and the expressions of MDA and α-SMA were gradually increased with time. GRP78 protein expression was decreased at 72 hours after paraquat administration., Conclusions: The results reveal that the expressions of α-SMA and GRP78 in paraquat poisoning group are up-regulated, suggesting ERS plays an important role in paraquat induced-pulmonary fibrosis.