(A) Definition of the different panels of protein mortality markers (1) histidine-rich glycoprotein (HRG) as a single protein biomarker performs best at time point 1. (2) Nine-protein panel consisting of the type-3 cystatins FETUB, KNG1, and HRG, the Inter-α-trypsin inhibitors ITIH1, ITIH2, and LCAT, HPR, SERPINA3, and AGT. (3) Sixteen-protein panel that includes next to the proteins of panel 2 also the type-3 cystatin AHSG, the Inter-α-trypsin inhibitors ITIH3, ITIH4, the immunoglobulins A1 and A2, fibronectin FN1, IGFALS, and AGT. (B) Performance of the different multi-protein panels in our Ferrara cohort at time points 1, 2, and 3, depicted by using ROC curve analysis, revealing that the multi-protein panels outperform the single protein HRG as a mortality predictor. The 9-protein panel performs best, especially at the earliest time points just shortly after critically ill patients have entered the ICU.