objective To evaluate the differential diagnosis value of serum complement C3 in Adult-onset Still’s disease (AOSD) and sepsis. Methods 58 patients with AOSD and 50 patients with sepsis were collected from Jiangsu Provincial People's Hospital from 2016 to 2019. 50 physical examinees of Jiangsu Provincial People's Hospital were selected as health control. Serum complement C3 levels in the three groups were detected, and differences in other laboratory indicators between AOSD patients and sepsis patients were compared. Univariate and multivariate factors were used to analyze the relationship between each variable and the occurrence of AOSD. ROC curve was used to explore the diagnostic efficacy of complement C3 and serum ferritin levels on AOSD and sepsis. Results AOSD group C3 level (1.49±0.24) is significantly higher than sepsis group (1.00±0.37), in addition, two groups of data in the high density lipoprotein cholesterol, ferritin, C3 differences statistically significant.In multivariate analysis,ferritin≥472.20ng/ml(OR56.968,95%CI2.218~1463.439,P<0.05),C3≥1.20g/L（OR27.801，95%CI3.217~240.277,P<0.01）and high density lipoprotein cholesterol≥0.82mmol/L（OR13.335，95%CI 1.009~176.293,P<0.05） independently suggested sepsis more than AOSD. The area under the curve (AUC) of serum C3 in the differential diagnosis of AOSD and sepsis was 0.81 (95% CI 0.63~1.00), and the diagnostic sensitivity and specificity were 0.90 and 0.73 when C3 critical value was 1.21, which reached the maximum diagnostic efficacy. However, when C3 combined with ferritin was used for differential diagnosis, the AUC was 0.86 (95%CI 0.75~0.96). Conclusion Serum C3 can be used as a differential diagnostic index of AOSD and sepsis, and has clinical value in the diagnosis of AOSD.