Objective: To compare the effects of intratracheal instillation by lumbar spinal needle (the best modeling approach explored by our group in the early stage) and intratracheal atomization on bleomycin-induced pulmonary fibrosis model in mice, so as to find out the optimal modeling method. Methods: Seventy-two C57BL/6J mice were randomly divided into blank group, lumbar spinal needle group, and aerosolization group, according to body weight, with 24 in each group. Mice in the blank group were given intratracheal instillation of saline. Mice in the lumbar spinal needle group were instilled with bleomycin in trachea, and mice in the aerosolization group was aerosolized with bleomycin in trachea by microsprayer aerosolizer. On 14th day and 21st day, Micro-CT, histopathological changes, hydroxyproline level, collagen immunohistochemistry and α-SMA protein expression were examined to evaluate the degree of pulmonary fibrosis in each group. Results: Compared with the blank group, the mice in the two model groups showed listlessness and slow response. Compared with the blank group, the weight of mice in the two model groups decreased significantly on 14th and 21st days (P < 0.01). Micro-CT results showed that the white shadows in the lumbar spinal needle group surrounded the trachea, while those in the aerosol group were more diffuse. The degree of alveolitis and pulmonary fibrosis was the highest in the aerosolization group, with a time-dependent trend. The hydroxyproline content in the two model groups increased significantly on day 14 and day 21 after modeling (P<0.05). And the increase of hydroxyproline concentrations on day 21 was more significant and stable (P<0.001). The expression of Collagen I in the two model groups increased significantly after 21 days of modeling, especially in the aerosolization group. The results of α-SMA protein detection showed that the expression of α-SMA in the two model groups was significantly higher than that in the blank group after 21 days (P<0.01). However, there was no significant difference between the two model groups. Conclusion: Intratracheal atomization of bleomycin is an optimized scheme for the establishment of pulmonary fibrosis models.