Lymphomas, particularly aggressive non-Hodgkin lymphomas (NHL), remain challenging due to poor outcomes in a subset of patients who fail initial therapy. Current minimally invasive biomarkers for risk stratification need further improvement. Immune checkpoint inhibitors (ICIs), while with limited efficacy in NHL, highlight the immune system's crucial role in cancer control. This study investigated the predictive and prognostic potential of soluble immune checkpoints (sICs) and their membrane-bound isoforms in the peripheral blood of lymphoma patients. Levels of sCD27, sCD28, and sCD80 were measured using multiplex immunoassay in 100 lymphoma patients and 62 healthy donors (HD). Expression of membrane-bound isoforms on PBMCs was analyzed via flow cytometry in 40 patients and 10 HD. All three sICs were significantly higher in lymphoma patients compared to HD. High levels were associated with significantly impaired disease control (DC) and survival at 12 and 24 months, progression free-survival (PFS) and overall survival (OS). The highest prediction capacity was achieved when assessing all three molecules in a combined score (p < 0.001, p = 0.013, for score 0 vs 3: DC:85% vs 18.5%, OS:87% vs 27%). Integrating expression of related membrane-bound markers on PBMCs led to a highly robust peripheral blood-based biomarker score comprising the soluble and membrane-bound compartments (2COMPIC-Score:3 sICs + 7 PBMC subsets) (p < 0.001, HR = 18.1;p = 0.001,HR = 19.2), corroborated by multivariate analysis, outperforming the clinically validated NCCN-IPI prognostic score. We unveil the potential of combining different minimally invasive liquid biopsy-based immune checkpoint assessments into a robust clinical score for prognostic prediction in lymphoma, mainly B(cell)-NHL. Pending prospective validation, our findings could aid clinicians in guiding therapeutic decisions.