The objective was to evaluate the effect of the gender, size, and tumor location at the time of the diagnosis on the regression response of choroidal melanoma following plaque radiotherapy treatment. The paper is a longitudinal prospective study of 28 patients diagnosed with choroidal melanoma at McGill University Health Centre from 1997 to 2002. All patients were treated with episcleral iodine-125 (I125) plaque radiotherapy. Plaques were inserted at the tumor site under echographic visualization. All patients had medium-size tumors, except for three. Patients had periodic ophthalmic evaluation at 3 and 6 months post radiation treatment, followed by 6-month intervals thereafter. Patients' mean age was 62 ± 15 years, 16 males and 12 females. Fifty percent of the tumors were located posterior to the equator with significant reduction in size at 12 months post plaque radiotherapy treatment. Significant regression was observed in all the tumor diameters at 5 years post treatment follow-up. Reduction in the depth diameter was significant (P < 0.01) in both male and female groups post treatment. There was a 25% (P < 0.001) reduction in the medium size of tumors at 5-year follow-up. Tumors located posterior to the equator responded best to I125 plaque radiotherapy. Male patients responded better than females to treatment. Medium-size melanoma responded well to plaque radiotherapy.