The role of cigarette smoking in the development and outcome of pulmonary fibrosis is uncertain. In this study, we aimed to assess the effect of route of bleomycin exposure in the development of pulmonary fibrosis and the effects of cigarette smoke on bleomycin-induced lung fibrosis. We studied five groups of rats; 1-control group, 2-intratracheal bleomycin (IT), 3- intratracheal bleomycin plus cigarette smoke for 4 wk (IT-S), 4- inhaled bleomycin (IN), 5- inhaled bleomycin plus cigarette smoke for 4 wk (IN-S). According to Aschoft's criteria, fibrosis score was higher in IT and IT-S compared to control, IN and INS groups. There was no significant difference between IT and IT-S groups. Histopathological evaluation of the lungs of rats revealed that neutrophils, macrophages, plasma cells and lymphocytes in alveolar interstitial space were significantly higher in IT and IT-S compared to IN and IN-S (p < 0.001). IT and IT-S showed a severe collagen, laminin, elastin, fibronectin and proteoglican levels in alveolar, vascular, airway and interstitial space. IN and IN-S showed mild inflammation in lung. There were alveolitis, edema, peribronchial fibrosis, fibroblast proliferation and emphysematous lesions in all groups except for the control group. In this study, we showed that in the development of pulmonary fibrosis in rats, intratracheal administration of bleomycin is more effective than bleomycin inhalation and smoking has no additional effect on development of fibrosis.