Field experiments were conducted on two North Carolina research stations in 1999, 2000, and 2001; on-farm in Lenoir, Wayne, and Wilson counties, NC, in 2002; and on-farm in Port Royal, VA, in 2000, 2001, and 2002 to evaluate possible gains from site-specific herbicide applications at these locations. Fields were scouted for weed populations using custom software on a handheld computer linked to a Global Positioning System. Scouts generated field-specific sampling grids and recorded weed density information for each grid cell. The decision aid HADSS™ (Herbicide Application Decision Support System) was used to estimate expected net return and yield loss remaining after treatment in each sample grid of every field under differing assumptions of weed size and soil moisture conditions, assuming the field was planted with either conventional or glyphosate-resistant (GR) soybean. The optimal whole-field treatment (that treatment with the highest expected net return summed across all grid cells within a field) resulted in average theoretical net returns of $79/ha (U.S. dollars) and $139/ha for conventional and GR soybean, respectively. When the most economical treatment for each grid cell was used in site-specific weed management, theoretical net returns increased by $13/ha (conventional) and $4.50/ha (GR), and expected yield loss after treatment was reduced by 10.5 and 4%, respectively, compared with the whole-field optimal treatment. When the most effective treatment for each grid cell was used in site-specific weed management, theoretical net returns decreased by $18/ha (conventional) and $4/ha (GR), and expected yield loss after treatment was reduced by 27 and 19%, respectively, compared with the whole-field optimal treatment. Site-specific herbicide applications could have reduced the volume of herbicides sprayed by as much as 70% in some situations but increased herbicide amounts in others. On average, the whole-field treatment was optimal in terms of net return for only 35% (conventional) and 57% (GR) of grid cells.