Importance Prevention of diabetic retinopathy is important to keep vision and quality of life. Objective To examine the effects of an intensive multifactorial intervention and hypoglycemia on retinopathy in people with type 2 diabetes. Design, Setting, and Participants J-DOIT3 (Japan Diabetes Optimal Integrated Treatment Study for 3 Major Risk Factors of Cardiovascular Diseases) is a multicenter, open-label, parallel-group randomized clinical trial that examined the efficacy of an intensified multifactorial intervention on cardiovascular outcomes and mortality in people with type 2 diabetes aged 45 to 69 years with hypertension and/or dyslipidemia. The study was conducted at 81 sites in Japan from June 2006 to March 2009, and data analysis was performed from September 2018 to August 2025. Interventions Participants were randomly assigned to intensive therapy for glucose, blood pressure, and lipids or conventional therapy and were followed up for a median duration of 8.5 years. Main Outcomes and Measures This study is a secondary analysis of retinopathy events of the secondary outcomes, composed of onset of retinopathy, progression of retinopathy, and loss of vision likely due to retinopathy. Results Among 2540 total participants (5080 eyes) randomly assigned to intensive therapy or conventional therapy, mean (SD) age was 59.0 (6.3) years, and 965 participants (38.0%) were female. Intensive therapy was associated with a risk reduction in onset of retinopathy (hazard ratio [HR], 0.83; 95% CI, 0.70-0.98; P = .03) but not with progression of retinopathy (HR, 1.02; 95% CI, 0.70-1.49; P = .93). Hemoglobin A 1 c (HbA 1 c ) at 1 year after randomization was associated with onset (HR, 1.31; 95% CI, 1.13-1.51; P &lt; .001), even after adjustment for baseline risk factors (ie, lower body mass index, longer duration of diabetes, higher fasting plasma glucose, higher blood pressure, and comorbid nephropathy), with no clear HbA 1 c threshold observed. Moreover, compared with those without a hypoglycemic episode during the intervention, the risk of onset was higher in those with 0.5 hypoglycemic episodes per year or fewer (HR, 1.25; 95% CI, 1.02-1.53) and even higher in those with more than 1 hypoglycemic episode per year (HR, 1.85; 95% CI, 1.39-2.47). Conclusions and Relevance This secondary analysis of the J-DOIT3 randomized clinical trial shows that in a randomized clinical trial setting, higher HbA 1 c and nonsevere hypoglycemia are associated with higher risk of onset of retinopathy in people with type 2 diabetes, even when good glycemic management, with a very low incidence of severe hypoglycemia, is achieved, suggesting the importance of strict glycemic management without any hypoglycemia. Trial Registration ClinicalTrials.gov Identifier: NCT00300976