Purpose To explore the risk factors for central retinal vein occlusion (CRVO) by comparing a large sample of patients with healthy controls. Materials and Methods Multi-center case-control study. The study group includes patients affected by central retinal vein occlusion, confirmed angiographically, aged 50 years old or above (Group A). The control group includes healthy subjects without an history of retinal vein occlusion (Group B). Outcome measures: age, gender, active smoking, presence of uncontrolled arterial hypertension (uHTN), presence of the following comorbidities: diabetes mellitus type II (DMII), chronic liver disease (CLD), chronic kidney disease (CKD), thyroid disease (TD), systemic lupus erythematosus (SLE), hyperhomocystenemia (HHcy), dyslipidemia (DLip), carotid artery disease (CAD), glaucoma, atrial fibrillation (AF), migraine headache (MH), chronic obstructive pulmonary disease (COPD), obstructive sleep apnea syndrome (OSAS), history of myocardial infarction (MI). Odds-ratios were calculated with logistic regression analysis. Results A total of 203 patients (Group A) and 339 controls (Group B). Statistically-significant differences were found for the following variables: age (OR: 1.109 [1.081–1.138], p < .001), active smoking (OR: 2.048 [1.210- 3.466], p < .008), DMII (OR: 4.533 [2.097–9.803], p < .001), HHcy (OR: 4.507 [2.477–10.001 ], p < .001), DLip (OR: 2.255 [1.352–3.762], p  =  .002), CAD (OR: 6.632 [2.944- 14.942], p < .001), glaucoma (OR: 4.656 [2.031–10.673], < .001), OSAS (OR: 1.744 [1.023–2.975], < .041), uHTN (OR: 3.656 [2.247–5.949], < .001). No statistically-significant differences were found for the other variables. Conclusions Older age, active smoking, as well as presence of DMII, HHcy, DLip, CAD, glaucoma, OSAS, and uHTN, all increase the risk for CRVO. A comprehensive assessment of patients with CRVO is paramount. Adequate control of all the aforementioned risk factors is likely of great significance in reducing the incidence of CRVO among the general population, and it likely plays an important role in improving the prognosis following the occlusive event.