We studied 152 patients with Graves disease mild orbitopathy (GO), with a disease duration of <18 months, who had been euthyroid for at least 2 months after antithyroid drug or surgery, or 6 months after 131-Iodine. No patient received previous treatment for GO, except for local measures. Patients were randomized to receive either selenium (SE), an antioxidant (as selenium selenite, 100 (g b.i.d), or pentoxifylline (PF), an anti-inflammatory and antifibrotic agent (600 mg b.i.d.), or placebo (PL, b.i.d) tablets. The intervention lasted for 6 months, followed by a follow-up of another 6 months. Primary outcomes were: i) objective assessment of the eye changes by a blinded ophthalmologist; ii) subjective GO-QoL, using a disease-specific questionnaire. Secondary outcome were: i) Clinical Activity Score (CAS); ii) diplopia Gormans score; iii) tolerability and safety. At 6- and 12-month evaluations treatment with SE, but not with PF, resulted in a statistically significant improvement, as compared to PL, of eye involvement (P=0.012 and P=0.116, respectively) and QoL (P<0.0001 and P=0.570, respectively). SE was also more effective as compared to PF on both outcomes (0.043 and 0.0006, respectively). The CAS decreased in all groups, but the change was significantly greater in patients treated with SE. No effects of treatment was observed on the Gormans score. GO worsened in 2 patients of the PL group and 1 of the PF group; no patients treated with SE showed worsening of GO. SE was well tolerated, whereas PF caused gastrointestinal side effects in a substantial number of patients. In conclusion, SE administration over a 6-month period, as compared to PL or PF, significantly improved the eye involvement and the QoL in patients with mild GO. Thus, a 6-month course of SE should be offered to patients with mild GO.