objective To explore the clinical effect of Azithromycin combined with Methylprednisolone in the treatment of refractory Mycoplasma pneumonia. Methods A total of 46 patients with refractory Mycoplasma pneumonia admitted to our hospital from June 2016 to June 2019 were selected as the research subjects, and they were grouped according to the random number table method. The 23 patients in the reference group were treated with Azithromycin, and the 23 patients in the study group were treated with Azithromycin combined with Methylprednisolone. Serum inflammatory factors such as high-sensitivity C-reactive protein (hs-CRP), serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6),as well as the total number of T lymphocytes (CD3+), negative T cells (CD4+), positive T cells (CD8+) and the ratio of negative T cells to positive T cells (CD4+/CD8+) peripheral blood indexes were compared and analyzed, and the clinical efficacy of the two groups was observed. Results After treatment, the levels of hs-CRP, TNF-α and IL-6 in the two groups were lower than those in this group before treatment, and the differences were statistically significant (P<0.05).The levels of hs-CRP, TNF-α and IL-6 in the study group were lower than those in the reference group after treatment, the differences were statistically significant (P<0.05). After treatment, the levels of CD3+, CD4+, CD4+/CD8+of the two groups were higher than those in this group before treatment, and the level of CD8+ was lower than that in this group before treatment, the differences were statistically significant (P<0.05). After treatment, the levels of CD3+, CD4+,CD4+/CD8+in the study group were higher than those in the reference group, and the level of CD8+ was lower than that in the reference group, the differences were statistically significant (P<0.05). The total effective rate of treatment in the study group was higher than that in the reference group, the difference was statistically significant (P<0.05). Conclusion The effect of Azithromycin combined with Methylprednisolone in the treatment of refractory Mycoplasma pneumonia has been fully demonstrated, which can improve the clinical symptoms of patients and reduce inflammation, and has high clinical application value.