Field studies were conducted 2004 and 2005 to evaluate weed control following POST applications of glyphosate in combination with either S-metolachlor (premix formulation), pyrithiobac, or trifloxysulfuron in conjunction with glyphosate in second-generation glyphosate-resistant cotton (Roundup Ready Flex). These herbicides were applied in combination with glyphosate in a two-application program at the 2-leaf (LF) (followed by glyphosate alone at the 10-LF growth stage), 6-LF (following glyphosate alone at the 2-LF growth stage), or 10-LF (following glyphosate alone at the 2-LF growth stage) cotton growth stages. No differences in weed control between residual herbicide were observed for goosegrass, hemp sesbania, Johnsongrass, Palmer amaranth, redroot pigweed, sicklepod, or smellmelon. Optimum control of barnyardgrass and browntop millet was achieved with glyphosate plus S-metolachlor. No differences were observed among application timings for control of goosegrass, hemp sesbania, Johnsongrass, pitted morningglory, and smellmelon. Control of barnyardgrass, browntop millet, Palmer amaranth, redroot pigweed, and sicklepod was optimized with residual herbicide application at the 2- or 10-LF timing. No yield differences were observed between residual herbicides, and seed cotton yield averaged 2,800 kg/ha. Yield was maximized when residual herbicide was applied at the 2- or 10-LF growth stage (2,960 to 2,730 kg/ha). Analysis based on numerical yield at particular residual-herbicide application timings and calculated yield for each timing based on the percentage of a standard three-application glyphosate program indicated the most consistent residual-herbicide timing for optimizing yield in a reduced-input Roundup Ready Flex weed-control program occurred at the two-leaf growth stage. All reduced-input programs, however, resulted in cotton yield of at least 93% of that obtained with the standard program.