Chronic heart failure (HF) is associated with persistent inflammation and poor prognosis. Identifying subsets of patients with unique inflammatory profiles may aid in better risk stratification and precision therapies. Utilizing single-cell RNA-sequencing of peripheral immune cells (HF patients and healthy controls (HC) N=8) showed increased T-cell activation in HF, which was validated via flow cytometry of more than 120 HF patients and 55 HCs. (HF = 65% and HC = 53% activated CD4 T-cells p<0.0001). Since T-cell activation is mainly based on MHC- and co-stimulatory molecules, we studied antigen-presenting cells, to identify certain MHC-signatures that may promote aberrant T-cell activation. HLA-DR, HLA-DM and ICAM-1 were significantly changed in monocytes of HF patients (1,17-fold increase of ICAM-1 in HF p<0.0001), and ICAM-1 positively correlated with TREM-1, and HLA-DR expression levels. Suspecting that carrying certain HLA-molecules might associate with a worse prognosis, we performed HLA-sequencing on age and gender matched HF patients from a case-control-study (N=93; 46 dead and 47 alive). Within this cohort we identified HLA-DRB5*101, which belongs to the DR2-supertype, as a strong predictor for death while molecules belonging to the DR5-supertype seemed to be protective (Oddsratio of 4.0 and 0.2 respectively). To assess whether HLA-DRB5 selectively promotes immune dysregulation, we analysed monocytes from healthy DRB5-carriers and non-carriers via CITE-seq. DRB5-carriers showed signs of enhanced antigen presentation, expressing more HLA- and co-stimulatory molecules (HLA-DRA, CREB1, ICAM2), as well as pro-inflammatory genes (JAK2 and IL6R). We confirmed these findings in HLA-DRB5-silenced THP1-derived M0-macrophages, which globally downregulated the expression of MHC-II and adhesion molecules like ITGAM and ITGB1. qPCR analysis of THP1-cells confirmed this global effect, molecules like HLA-DPA and HLA-DRB1 were significantly downregulated following KD of HLA-DRB5. Thus, our data suggests a way to risk stratify HF patients with respect to their HLA-type and may provide novel therapeutic insights.