Field studies were conducted at four locations in North Carolina in 1998 and 1999 to evaluate the use of the Herbicide Application Decision Support System (HADSS?) for weed management in nontransgenic, bromoxynil-resistant, and glyphosate-resistant cotton. Weed management systems included trifluralin preplant incorporated (PPI) plus fluometuron preemergence (PRE) or no soil-applied herbicides. Postemergence (POST) options included bromoxynil, glyphosate, or pyrithiobac early POST (EPOST) followed by (fb) MSMA plus prometryn late postemergence-directed (LAYBY) or herbicide recommendations given by HADSS. Glyphosate-resistant systems provided control equivalent to or better than control provided by bromoxynil-resistant and nontransgenic systems for smooth pigweed, Palmer amaranth, large crabgrass, goosegrass, ivyleaf morningglory, and fall panicum. Trifluralin PPI fb fluometuron PRE fb HADSS POST provided equivalent or higher levels of weed control and yield than trifluralin PPI fb fluometuron PRE fb bromoxynil, glyphosate, or pyrithiobac EPOST fb MSMA plus prometryn LAYBY. The trifluralin PPI fb fluometuron PRE fb HADSS POST systems controlled large crabgrass at Goldsboro and fall panicum better than HADSS POST-only systems in nontransgenic cotton. Cotton yield and net returns in the glyphosate-resistant systems were always equal to or higher than the nontransgenic and bromoxynil-resistant systems. Net returns were higher for the soil-applied fb HADSS POST treatments in 8 of 12 comparisons with HADSS POST systems without soil-applied herbicides. Early-season weed interference reduced cotton lint yields and net returns in POST-only systems.