Objective To compare the effects of intratracheal instillation by lumbar spinal needle and intratracheal atomization on bleomycin-induced pulmonary fibrosis modeling in mice, to determine the optimal modeling method. Methods Seventy-two C57BL/6J mice were divided randomly into control, lumbar spinal needle and aerosolization groups, according to body weight (n= 24 mice per group). Mice in the control and lumbar spinal needle groups received intratracheal instillation of saline or bleomycin, respectively, and mice in the aerosolization group received aerosolized bleomycin intracheally by microsprayer aerosolizer. Micro-computed tomography (CT), histopathological changes, hydroxyproline(HYP) levels, Collagen Ⅰ(COLⅠ) and α-smooth muscle actin (α-SMA) protein expression were examined on days 14 and 21 to evaluate the degree of pulmonary fibrosis in each group. Results Mice in the two model groups showed listlessness, slow responses, and decreased body weights on days 14 and 21, compared with the control group (P<0.001). Micro-CT showed white shadows surrounding the trachea in the lumbar spinal needle group, while the shadows were more diffuse in the aerosol group. The degrees of alveolitis and pulmonary fibrosis were highest in the aerosolization group, with a time-dependent trend. The hydroxyproline contents were significantly increased in the two model groups on days 14 and 21 after modeling (P<0.05), with the increase on day 21 being more significant and stable (P<0.001). COLⅠ expression was significantly increased in both the lumbar spinal needle group and aerosolization group on days 21 after modeling, especially in the aerosolization group(P<0.001). Expression levels of α-SMA were significantly higher in the lumbar spinal needle group and aerosolization group compared with the control group on days 21 (P<0.001); however, there was no significant difference between the two model groups. Conclusions intratracheal atomization of bleomycin is the optimal method for establishing a mouse model of pulmonary fibrosis.