Background Both deficiency and, according to recent reports, excess of vitamin B12 (B12) are associated with increased mortality. Thus, it is difficult to estimate the effect of B12 on overall survival, which also depends on folate (FA) in homocysteine lowering. This study aimed to assess FA and B12 serum concentrations associated with long-term survival of vascular surgery patients by means of a prognostic index (PI). Methods This single-center, prospective cohort study comprised 485 consecutive carotid surgery patients. B-vitamin baseline concentrations of B12 and FA were used to compute a PI for postoperative overall survival from January 2003 to January 2012 (mean observation period 102.3 months). Results Increasing B12 serum concentrations showed a nonlinear association with overall survival ( P  = .033). A B vitamin-based PI significantly predicted overall (hazard ratio HR per standard deviation = 1.97, confidence interval CI 1.37-2.82; P  < .001), cardiovascular (HR = 3.03, CI 1.78-5.14; P  < .001), and stroke-free survival (HR = 2.20, CI 1.22-3.98; P  = .009), and revealed that the highest adverse event-free survival was predicted by high FA (16.3 ± 12.9 ng/mL) but only moderate B12 (360.3 ± 156.0 pmol/L) baseline concentrations. Conclusions Prediction of increased long-term overall, cardiovascular, and stroke-free survival is based on high FA but only moderate B12 serum concentrations. Excessive B12 concentrations might harbor a potential harm and are no requisite for low homocysteine concentrations. The association between B vitamins and survival might serve either as a tool for risk stratification or, if causative, as effective therapy, if optimal dosing of B vitamins is provided and on-treatment concentrations, including homocysteine and renal functions, are closely monitored.