Pancreatoduodenectomy may lead to new-onset diabetes mellitus, also known as type 3c diabetes, but the exact risk of this complication is unknown. The aim of this review was to assess the risk of new-onset diabetes mellitus after pancreatoduodenectomy. A literature search was performed in PubMed, Embase (Ovid), and the Cochrane Library for English articles published from March 1993 until March 2017 (PROSPERO registry number: CRD42016039784). Studies reporting on the risk of new-onset diabetes mellitus after pancreatoduodenectomy were included. For meta-analysis, studies were pooled using the random-effects model. All studies were appraised according to the Newcastle-Ottawa Scale. After screening 1,523 studies, 22 studies involving 1,121 patients were eligible. The mean weighted overall proportion of new-onset diabetes mellitus after pancreatoduodenectomy was 16% (95% confidence interval, 12%–20%). We found no significant difference in risk of new-onset diabetes mellitus when pancreatoduodenectomy was performed for nonmalignant disease after excluding patients with chronic pancreatitis (19% risk; 95% confidence interval, 7%–43%; 6 studies) or for malignant disease (22% risk; 95% confidence interval, 14%–32%; 11 studies), P = .71. Among all patients, 6% (95% confidence interval, 4%–10%) developed insulin-dependent new-onset diabetes mellitus. This systematic review identified a clinically relevant risk of new-onset diabetes mellitus after pancreatoduodenectomy of which patients should be informed preoperatively.