Objective: To investigate the clinical efficacy of human immunoglobulin combined with azithromycin in the treatment of severe mycoplasma pneumonia in children. Methods: 94 children with severe mycoplasma pneumonia admitted to our hospital from February 2022 to February 2024 were selected as the study objects. The children were divided into observation group and control group with 47 cases in each group by random number table method. The control group was treated with azithromycin. Observation group was treated with human immunoglobulin combined with azithromycin. The clinical efficacy, improvement time of symptoms and signs, immunoglobulin (Ig) levels (IgA, IgG, IgM), T lymphocyte subsets (CD3+, CD4+, CD8+, CD4+/CD8+), inflammatory factor levels [CRP), interleukin-6 (IL-6), tumor necrosis factor α(TNF-α)] and the occurrence of adverse reactions were analyzed and compared between the two groups. Results: The total effective rate of observation group was significantly higher than that of control group (P < 0.05). The improvement time of fever, cough and pulmonary rales in observation group was significantly shorter than that in control group (P < 0.05). After treatment, the levels of IgA, IgG and IgM in both groups were significantly higher than before treatment, and the levels of IgA, IgG and IgM in the observation group were significantly higher than those in the control group (P < 0.05). After treatment, CD3+, CD4+ and CD4+/CD8+ in both groups were significantly higher than before treatment, and CD8+ was significantly lower than before treatment. The levels of CD3+, CD4+ and CD4+/CD8+ in observation group were significantly higher than those in control group, and CD8+ was significantly lower than those in control group (P < 0.05). After treatment, serum CRP, IL-6 and TNF-α in both groups were significantly lower than before treatment. The serum CRP, IL-6 and TNF-α in the observation group were significantly lower than those in the control group (P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P > 0.05). Conclusion: Human immunoglobulin combined with azithromycin in the treatment of severe mycoplasma pneumonia in children can improve the efficacy, promote the improvement of symptoms and signs, improve body fluid and cellular immune function, inhibit inflammation, and have high safety.