Abstract: Objective To investigate the predictive value of serum macrophage migration inhibitory factor (MIF), monocyte chemoattractant factor-1 (MCP-1) levels combined with capillary leak index (CLI) for acute respiratory distress syndrome (ARDS) in patients with sepsis. Methods A total of 212 patients with sepsis were selected as the study subjects. Their clinical manifestations, chest X-ray plain film, and CT scan results were observed. The patients were divided into ARDS group (62 cases) and non-ARDS group (150 cases). The serum MIF and MCP-1 levels and CLI of the two groups were compared. Multivariate logistic regression analysis was used to screen the influencing factors for ARDS in patients with sepsis. The receiver operating characteristic (ROC) curve was employed to evaluate the predictive efficacy of relevant indicators for ARDS in patients with sepsis. Results The serum MIF and MCP-1 levels and CLI in the ARDS group were all higher than those in the non-ARDS group, with statistically significant differences (P < 0.05). The oxygenation index in the ARDS group was lower than that in the non-ARDS group, while the Acute Physiology and Chronic Health Evaluation Ⅱ(APACHE Ⅱ) score and Sequential Organ Failure Assessment (SOFA) score were higher than those in the non-ARDS group, with statistically significant differences (P < 0.05). Multivariate logistic regression analysis showed that a low oxygenation index, high APACHE Ⅱ score, high SOFA score, high serum MIF level, high serum MCP-1 level, and high CLI were all independent risk factors for ARDS in patients with sepsis (P < 0.05). The ROC curve demonstrated that the areas under the curve (AUCs) for predicting ARDS in patients with sepsis by MIF, MCP-1, and CLI alone and their combination were 0.902, 0.818, 0.708, and 0.932, respectively. The combined prediction had the highest efficacy, with a sensitivity of 96.77% and a specificity of 96.67%. Conclusion Serum MIF and MCP-1 levels and CLI are all closely related to ARDS in patients with sepsis. The combined application of these three indicators has a high predictive value for ARDS in patients with sepsis.