In this multicenter, intervention-concealed, randomized clinical trial of 2,760 critically ill patients hospitalized with sepsis, the use of a daily procalcitonin-guided protocol resulted in shorter antibiotic duration as compared with standard care, without a significant difference in 28-day all-cause mortality. There was no significant difference in antibiotic duration between patients managed with a daily C-reactive protein-guided protocol and standard care, and the difference in all-cause mortality between these two groups was inconclusive.