Due to a long history of extensive mercury mining and smelting activities, local residents in Wanshan, China, are suffering from elevated mercury exposure. The objective of the present study was to study the effects of oral supplementation with selenium-enriched yeast in these long-term mercury-exposed populations. One hundred and three volunteers from Wanshan area were recruited and 53 of them were supplemented with 100 μg of organic selenium daily as selenium-enriched yeast while 50 of them were supplemented with the nonselenium-enriched yeast for 3 months. The effects of selenium supplementation on urinary mercury, selenium, and oxidative stress-related biomarkers including malondialdehyde and 8-hydroxy-2-deoxyguanosine were assessed. This 3-month selenium supplementation trial indicated that organic selenium supplementation could increase mercury excretion and decrease urinary malondialdehyde and 8-hydroxy-2-deoxyguanosine levels in local residents.