BACKGROUND AND OBJECTIVE: Uveal melanoma is the most common primary intraocular cancer; however, the molecular features that predict response to therapy are poorly understood. Our objective was to determine whether gene expression profiling (GEP) is associated with rate of tumor regression after I-125 plaque brachytherapy for uveal melanoma. PATIENTS AND METHODS: Retrospective review of 138 patients with posterior uveal melanoma treated with I-125 plaque brachytherapy in which GEP class and 3-month post-radiation ultrasonographic tumor thickness data were available. Statistical analysis was performed using t test and Fisher's exact test. RESULTS: GEP class assignment was class 1 in 83 (60.1%) and class 2 in 55 (39.9%) patients. Mean patient age was 60.9 years for class 1 and 68.1 years for class 2 tumors (P = .002). Mean initial tumor diameter was 13.0 mm for class 1 and 14.1 mm for class 2 tumors (P = .02). Mean initial tumor thickness was 5.2 mm for class 1 and 6.1 mm for class 2 tumors (P = .047). Three months after I-125 plaque radiotherapy, mean reduction in tumor thickness was 26.5% for class 1 and 16.7% for class 2 tumors (P = .03). CONCLUSION: Class 1 uveal melanoma tumors exhibit more rapid early tumor regression than class 2 tumors after I-125 plaque radiotherapy.