Background: Elevated plasma vitamin B12 concentrations were identified as predictors of mortality in patients with oncologic, hepatic and renal diseases, and in elderly and critically ill medical patients. The association between vitamin B12 concentrations and in-hospital mortality in adult patients at nutritional risk has not been assessed. Methods: In this five-year prospective study, we investigated whether high vitamin B12 concentrations (>1000 pg/mL) are associated with in-hospital mortality in 1373 not-bed-ridden adult patients at nutritional risk (Nutrition Risk Index <97.5), admitted to medical and surgical departments. Results: Three hundred and ninety-six (28.8%) patients presented vitamin B12 > 1000 pg/mL. Two hundred and four patients died in the hospital (14.9%). The adjusted odds ratio of in-hospital mortality in patients with high vitamin B12 was 2.20 (95% CI, 1.56-3.08; p < 0.001); it was independent of age, gender, body mass index, six-month previous unintentional weight loss, admission ward, presence of malignancy, renal function, C-reactive protein and prealbumin. Patients with high vitamin B12 also had a longer length of stay (LOS) than those with normal concentrations (median 25 days, (IQR 15-41) versus 23 days (IQR 14-36); p = 0.014), and elevated vitamin B12 was an independent predictor of LOS (p = 0.027). Conclusions: An independent association between elevated vitamin B12 concentrations, mortality and LOS was found in our sample of hospitalized adult patients at nutritional risk. Although the underlying mechanisms are still unknown and any cause-effect relation cannot be inferred, clinicians should be aware of the potential negative impact of high vitamin B12 concentrations in hospitalized patients at nutritional risk and avoid inappropriate vitamin supplementation.

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