A study was conducted in 2004 and 2005 to evaluate the benefit of applying fluometuron PRE versus glyphosate-only POST programs in second-generation GR cotton (Roundup Ready Flex®). Fluometuron was either included or excluded with POST application timings of glyphosate at the following cotton growth stages: (1) 3 leaf (lf) followed by (fb) 7 lf fb 14 lf (over the top) OT (2) 3 fb 7 lf OT (3) 7 lf OT fb 14 lf postemergence directed (PD), and (4) 7 fb 14 lf OT. Control of goosegrass, Palmer amaranth, pitted morningglory, sicklepod, and smellmelon was increased 2 to 8 percentage points with the addition of fluometuron PRE. The inclusion of fluometuron PRE did not improve control of barnyardgrass, browntop millet, hemp sesbania, johnsongrass, or redroot pigweed and control ranged from 81% to 84%, 69% to 75%, 94% to 94%, 87% to 89%, and 92% to 93%, respectively. By 56 d after the last POST application, control of johnsongrass, Palmer amaranth, pitted morningglory, and smellmelon was at least 83%, 93%, 92%, and 86%, respectively, with only slight differences noted among POST glyphosate programs. Control of barnyardgrass, browntop millet, and redroot pigweed was 68%, 47%, 86%, respectively, with the POST glyphosate program of 3 fb 7 lf OT, which was significantly less than all other glyphosate POST programs. Cotton yield increased 32% and 36% with the addition of fluometuron PRE to glyphosate POST programs consisting of 7 lf OT fb 14 lf PD and 7 lf fb 14 lf OT, respectively. Cotton yield for other glyphosate POST programs including an earlier 3 lf application was not improved when fluometuron was applied PRE. Without inclusion of fluometuron PRE, yield was maximized with the glyphosate POST program that included three applications of glyphosate (2,510 kg/ha). Overall, this research emphasizes the fact that weed control is important in the early season as well as in the late season in second-generation GR cotton.