Total N-glycome in blood serum or plasma provides information about all serum/plasma protein enzymatic glycosylation, a tightly regulated cotranslational and post-translational modification. Total plasma/serum N-glycome has shown specific patterns (signatures) in patients with high-mortality pathologies, such as cancer and cardiovascular diseases; thus, we explored the capacity of total serum N-glycome to predict mortality in a general adult population. This prospective cohort study was performed in a municipality in Spain including a random sample of 1516 adults. Participants were profiled for total serum N-glycome at baseline. Serum enzymatic N-glycan release was performed on a robotic platform followed by hydrophilic interaction chromatography–ultraperformance liquid chromatography glycan separation. The computerized medical records were checked at a median follow-up of 7.52 years to collect the date and cause of all deaths. N-glycan groups from total serum were used to develop mortality prediction models. Total serum N-glycome peak (GP) 16, mainly composed of A2[3]BG1S[3]1, predisposed to all-cause mortality; GP 22, mainly composed of FA2G2S[6]1, protected from all-cause mortality. The balance between them predicted allcause mortality incidence over time (area under the curve [AUC], 0.810 [0.773–0.847]). Similar results were obtained for cancer mortality, with GPs 16, 17, 22, and 23 (AUC, 0.786 [0.728–0.843]); and for cardiovascular mortality, with GPs 7 and 9 (AUC, 0.747 [0.645–0.850]). Their predictive powers had an independent and additive effect on classical prediction factors. The balances between specific GPs are independent predictors of all cause, cancer, and cardiovascular mortality and could contribute significantly to improving prognostic tools.