Background: There is a lack of documented real-world evidence about the efficacy of current therapeutics for autoimmune inflammatory rheumatic diseases (AIIRD)-associated adult macrophage activation syndrome (MAS). Objective: To analyze the efficacy of different treatments, especially plasma exchange (PE), in AIIRD-associated MAS. Methods: Among 5775 patients with AIIRD in Tongji Hospital from 2014 to 2020, 62 AIIRD-associated MAS cases were collected. Unadjusted logistic regression, least absolute shrinkage and selection operator (LASSO), and inverse probability of treatment weight (IPTW) analyses were used to characterize the clinical features and potential factors related to the prognosis. Paired t-test was used to compared the changes of inflammatory indicators before and after PE treatment. Results: The baseline data was defined as the data collected at the onset of MAS, and all of the 62 patients were diagnosed as AIIRD before MAS onset. The prevalance rate of MAS in AIIRD was 1.1%, and the most common types of AIIRD were systemic lupus erythematosus (45.2%) and adult-onset Still's disease (33.9%). All 62 MAS patients received glucocorticoids, 87.1% patients used at least one immunosuppressive agent, and 54.8% received PE. LASSO regression indicates a positive effect of PE on the basis of variables. After PE treatment, serum levels of multiple inflammatory cytokines were rapidly reduced, accompanied by improvements in clinical symptoms and laboratory indecies including ferritin, lactate dehydrogenase, and C-reactive protein. LASSO regression indicates that PE treatment was associated with a marked reduction of mortality (from 53.6% to 11.8%), with a hazard ratio (HR) of 0.148 (p < 0.001) after adjustment for confounding factors using IPTW analysis. Conclusion: With the background therapy of glucocorticoids and immunosuppressive agents, PE is an effective approach to rapidly clear inflammatory cytokines and reduce mortality of AIIRD-associated MAS.