Aims Impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes arise due to insufficient insulin secretion and are risk factors for cardiovascular (CV) events. Thus, targeting normal fasting glucose levels with insulin may reduce CV events. Previous studies suggest that ω-3 fatty acid supplements may reduce CV death; however, their effect in high-risk dysglycemic individuals is not known. Methods People aged ≥50 years with evidence of CV disease and with IFG, IGT, newly detected or established diabetes (on 0 or 1 oral agent), and a local glycated hemoglobin b150% of the upper limit of normal for that assay were recruited and allocated to (a) either 1 daily injection of insulin glargine with the dose titrated to achieve a fasting plasma glucose ω5.3 mmol/L (95 mg/dL), or standard glycemic care; and (b) either ω-3 Cacid ethyl esters 90 (1 g consisting of EPA 465 mg and DHA 375 mg) or identical placebo, according to a 2 × 2 factorial design. The 2 different primary outcomes for the insulin and ω-3 fatty acid arms are CV events and CV death, respectively. Results A total of 12612 (mean age 64, 35% women) people in 40 countries were randomized during a 2-year period ending December 2005. Eighty-two percent had established diabetes, 6% had new diabetes, and 12% had IGT or IFG; the mean fasting plasma glucose was 7.3 mmol/L (131 mg/dL). Conclusions The ORIGIN trial will determine whether or not either or both of these interventions can reduce CV events.