Objective?To explore the clinical effect of imipenem cilastatin and vancomycin in the treatment of severe pneumonia induced by Gram-positive bacteria, and to provide reference for the optimization of treatment plan. Methods?A total of 94 patients with severe pneumonia induced by Gram-positive bacteria admitted to Dingxi People’s Hospital were enrolled between October 2019 and October 2021. They were randomly divided into group A and group B, 47 cases in each group. The group A was treated with imipenem and cilastatin sodium, while group B was treated with vancomycin. After 14 days of treatment, curative effect, treatment situations, bacterial clearance, inflammatory factors and adverse reactions were compared between the two groups. Results?After 14 days of continuous treatment, total response rate of treatment and bacterial clearance in group A were better than those in group B (P ＜0.05). Antipyretic time, mechanical ventilation time and stay time in ICU were shorter than those in group B (P ＜0.05). After treatment, levels of high-sensitivity C-reactive protein (hs-CRP) and procalcitonin (PCT) in both groups were lower than those before treatment, which were lower in group A than group B (P ＜ 0.05). The incidence of adverse reactions in group A was lower than that in group B (P ＜ 0.05). Conclusion?Compared with vancomycin, curative effect of imipenem cilastatin is better on severe pneumonia induced by Gram-positive bacteria, which can effectively inhibit inflammation response and accelerate recovery process of patients, with higher safety.