Context: Previous association studies suggest the development of Graves' orbitopathy (GO) is variably influenced by environmental risk factors. Objective: To determine the risk factors and predict odds for developing GO in Graves' hyperthyroidism (GH). Design: Case-control study. Setting: Multi-centre Australian Thyroid-associated Orbitopathy Research group consisting of tertiary endocrinology and ophthalmology outpatients and related private practices. Patients or Other Participants: A total of 1042 participants with GH were designated as cases if they had GO (n = 604) and controls if they did not have GO (n = 438). Main Outcome Measures: Primary outcome was GO risk factors and secondary outcome was dysthyroid optic neuropathy (DON) with the effects of risk factors measured by odds ratio (OR) using multiple logistic regression, adjusted for known risk factors and exploratory variables. Results: The odds of GO increased by 17% for each decade increase in the age of onset of GH (OR 1.17, confidence interval (CI): 1.06-1.29; P =.002) and by 7% for each year increase in the duration of GH (OR 1.07, CI: 1.05-1.10; P <.001). Smoking increased the odds for GO by 2.22 for current smoker and 2.07 for exsmoker (P <.001), compared with never smoking. The odds of GO are 86% less in Graves' patients using antithyroid medication than those not (OR 0.14, CI: 0.06-0.34; P <.001). Predictors for DON were older age, oculomotility restriction, strabismus, reduced palpebral aperture, and active GO. Conclusions: This study identified increase age of onset, duration of GH, and smoking as risk factors for GO. Usage of antithyroid medication was negatively related to GO. Older patients with restricted ocular motility, strabismus, and active GO are at higher risk of DON and may benefit from early medical intervention.