PURPOSE: To evaluate regression rates after plaque radiotherapy and thermotherapy of uveal melanoma with chromosome 3 monosomy versus disomy. DESIGN: Noncomparative case series. PARTICIPANTS: Two hundred and seventy patients with uveal melanoma. METHODS: Fine needle aspiration biopsy was used at the time of plaque radiotherapy to sample tumor cells for genetic testing. MAIN OUTCOME MEASURES: Tumor thickness regression based on chromosome 3 status. RESULTS: At the time of plaque radiotherapy, the median tumor thickness was 4.0 mm for melanomas with chromosome 3 monosomy and 3.5 mm for those with disomy 3. The median tumor thickness (% original thickness) at 4, 8, 12, 15, and 18 months after radiotherapy for melanoma with monosomy 3 was 77%, 67%, 58%, 55%, and 50% and for those with disomy 3 was 82%, 70%, 69%, 67%, and 61%. The median monthly regression rate was 3.1% for tumors with monosomy 3 and 2.7% for those with disomy 3. The overall regression and monthly rate of regression was statistically greater at 12 months (P < 0.001) and 15 months (P = 0.003) for melanomas with monosomy 3 compared with disomy 3. CONCLUSIONS: Uveal melanomas with chromosome 3 monosomy showed faster and greater tumor thickness regression at 12 and 15 months after plaque radiotherapy and thermotherapy than melanomas with disomy 3.