Background Certain inflammatory biomarkers increase with age, provide information about general burden of illness and could cause or reflect any collateral damage to healthy cells and organs. However, comparative studies to predict adverse outcomes are missing. Therefore, our study validated and identified the principal prognostic marker to predict important adverse outcomes in the oldest old from an extensive battery of serum inflammatory markers. Methods A large battery of potential ‘inflammaging’ markers (IL-1α, IL1-β, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, EGF, VEGF, MCP-1, usCRP, prealbumin) was assessed in a representative sample of 415 heterogenic individuals 80years of age or older in the BELFRAIL study. Kaplan–Meier, Cox proportional hazards and CART analyses determined the overall prognostic value of these markers for predicting all-cause, cardiovascular and non-cardiovascular mortality as well as hospitalization. Results Serum IL-6 and usCRP levels were strongly associated with time of survival, independent of cause of death. Serum IL-6 levels had the most robust dose–response relationship with mortality. To a lesser extent, IL-10 and IL-1β were associated with all-cause mortality but were restricted to non-cardiovascular or cardiovascular mortality, respectively. Having a low IL-6 at baseline (<1.77pg/ml) could predict 90% of those who were not at risk for all-cause mortality after 3years, even after adjusting for confounders. Similarly, we observed an 83.6% chance of identifying those cases with 0 or 1 hospitalization using low IL-6 serum levels. Conclusion The results suggest that a single measurement of low IL-6 serum levels is the first choice to guide clinical practice in the oldest old and could summarize the short-term risk of death and hospitalization.