Background: To evaluate impact of spironolactone (S) on pulmonary toxicity of concomitant use of thoracic radiotherapy (RT) and trastuzumab (T).  Materials and Methods: Eighty rats were divided into eight groups: group (G) 1 was control group; G2, G3 and G4 were RT, S and T groups; G5, G6, G7 and G8 were RT+T, T+S, RT+S and RT+T+S groups respectively. Rats were sacrificed at 6 hour, 21 and 100 day after RT and lung samples were retrieved. Results: By 100th days of RT inflammation score, lung fibrosis score and TGF- expression were significantly different within study groups (p values were 0.002, 0.001 and 0.043 respectively). Inflammation score of G8 was significantly lower than inflammation scores of G2 and G5 (p values: G2-G8= 0.004, and G5-G8=0.022). Inflammation score of G2 was significantly higher than G7 (p=0.028). There were significant differences regarding to fibrosis scores between G2-G8 (p=0.015), G2-G7 (p=0.017) and G5-G8 (p=0.011). TGF-β expression was higher in both G2 and G5 when compared to G8 (p = 0.038). Conclusion: Our results suggested that S is an effective treatment option for improving radiation-induced pulmonary fibrosis. These findings should be clarified with further preclinical and clinical studies.