Objective To investigate the expression of S100A12 protein in peripheral blood of patients with acute respiratory distress syndrome (ARDS) and its clinical significance. Methods Sixty ARDS patients admitted between October 2015 and December 2016 were included in the study. They were divided into a mild group (n=20), a moderate group (n=20) and a severe group (n=20) according to the oxygenation state. Meanwhile they were divided into a survival group (n=37) and a death group (n=23) according to the 30-day prognosis. Sixty simultaneous healthy subjects were selected as a control group. The clinical data of all subjects were collected. Fasting venous blood was collected in the morning for measurement of S100A12 expression in peripheral blood by ELISA method. Results Compared with the control group, the levels of S100A12, interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α) in peripheral blood and APACHEⅡ score were significantly increased in the ARDS patients, and PaO 2/FiO 2 was significantly decreased (all P<0.05). The level of S100A12 in peripheral blood was positively correlated with the severity of ARDS. The level of S100A12 was much higher in the severe group than that in the moderate group and the mild group, and higher in the moderate group than that in the mild group (allP<0.05). Correlation analysis showed that S100A12 level in peripheral blood of the ARDS patients was positively correlated with IL-1, TNF-α and APACHEⅡ score (P<0.05), but negatively correlated with PaO 2/FiO 2 (P<0.05). Logistic regression analysis showed that IL-1, TNF-α, APACHEⅡ score and S100A12 were independent risk factors for prognosis of ARDS. PaO 2/FiO 2 was an independent protective factor for prognosis of ARDS. ROC curve analysis showed that the S100A12 level had a certain predictive value for ARDS and could be used as a prognostic indicator. Conclusions The level of S100A12 in peripheral blood of ARDS patients is significantly increased and is closely related to the severity of ARDS. It has a potential clinical value for early diagnosis, treatment and prognosis of ARDS.