OBJECTIVE: To synthesize updated evidence on the cost-effectiveness (CE) of interventions to manage diabetes, its complications, and comorbidities. RESEARCH DESIGN AND METHODS: We conducted a systematic literature review of studies from high-income countries evaluating the CE of diabetes management interventions recommended by the American Diabetes Association (ADA) and published in English between June 2008 and July 2017. We also incorporated studies from a previous CE review from the period 1985-2008. We classified the interventions based on their strength of evidence (strong, supportive, or uncertain) and levels of CE: cost-saving (more health benefit at a lower cost), very cost-effective (≤$25,000 per life year gained [LYG] or quality-adjusted life year [QALY]), cost-effective ($25,001-$50,000 per LYG or QALY), marginally cost-effective ($50,001-$100,000 per LYG or QALY), or not cost-effective (>$100,000 per LYG or QALY). Costs were measured in 2017 U.S. dollars. RESULTS: Seventy-three new studies met our inclusion criteria. These were combined with 49 studies from the previous review to yield 122 studies over the period 1985-2017. A large majority of the ADA-recommended interventions remain cost-effective. Specifically, we found strong evidence that the following ADA-recommended interventions are cost-saving or very cost-effective: In the cost-saving category are ) ACE inhibitor (ACEI)/angiotensin receptor blocker (ARB) therapy for intensive hypertension management compared with standard hypertension management, ) ACEI/ARB therapy to prevent chronic kidney disease and/or end-stage renal disease in people with albuminuria compared with no ACEI/ARB therapy, ) comprehensive foot care and patient education to prevent and treat foot ulcers among those at moderate/high risk of developing foot ulcers, ) telemedicine for diabetic retinopathy screening compared with office screening, and ) bariatric surgery compared with no surgery for individuals with type 2 diabetes (T2D) and obesity (BMI ≥30 kg/m). In the very cost-effective category are ) intensive glycemic management (targeting A1C <7%) compared with conventional glycemic management (targeting an A1C level of 8-10%) for individuals with newly diagnosed T2D, ) multicomponent interventions (involving behavior change/education and pharmacological therapy targeting hyperglycemia, hypertension, dyslipidemia, microalbuminuria, nephropathy/retinopathy, secondary prevention of cardiovascular disease with aspirin) compared with usual care, ) statin therapy compared with no statin therapy for individuals with T2D and history of cardiovascular disease, ) diabetes self-management education and support compared with usual care, ) T2D screening every 3 years starting at age 45 years compared with no screening, ) integrated, patient-centered care compared with usual care, ) smoking cessation compared with no smoking cessation, ) daily aspirin use as primary prevention for cardiovascular complications compared with usual care, ) self-monitoring of blood glucose three times per day compared with once per day among those using insulin, ) intensive glycemic management compared with conventional insulin therapy for T2D among adults aged ≥50 years, and ) collaborative care for depression compared with usual care. CONCLUSIONS: Complementing professional treatment recommendations, our systematic review provides an updated understanding of the potential value of interventions to manage diabetes and its complications and can assist clinicians and payers in prioritizing interventions and health care resources.