Episcleral plaque radiotherapy is a widely applied treatment for selected patients with uveal melanomas. This treatment is well tolerated but may produce severe late radiation complications resulting in decreased visual acuity that reduces the attractiveness of conservative therapy. The purpose of this study was to access if the addition of episcleral hyperthermia decreases late radiation complications through radiation dose reduction while maintaining high incidence of local tumor control. In a 3-year period, episcleral plaque thermoradiotherapy was given to 25 patients with uveal melanoma in a Phase I study. The mean tumor height was 6.2 mm and the mean tumor basal area was 173 mm(2). The mean radiation dose given to the tumor apex was 72.2 Gy and the mean hyperthermia temperature, given once for 45 min, was 43.5 degrees C. Of the 25 patients treated, 22 (88%) showed tumor height reduction, 2 (8%) showed no change, and 1 (4%) had an increase in tumor height. At the last follow-up (range, 20-68 months; mean, 31.2 months), a 43% mean tumor height reduction was recorded (p = 0.0002). Of the 22 patients initially showing tumor regression, 2 (9%) had subsequent tumor progression. At least ambulatory vision (>5/200) was maintained by 20 (80%) patients. Severe complications, including hemorrhagic retinal detachment and a large vitreous hemorrhage, were seen in 2 (8%) patients early in this Phase I study. The treatment program was well tolerated by the study patients. Severe late treatment toxicity was sharply reduced by limiting the mean scleral temperature to < or equal to 44 degrees C. This study employing 30% lower radiation doses, showed tumor regression in the majority of patients. Longer follow-up is needed to assess long-term treatment efficacy and late treatment complications.