An experiment was conducted at five locations in North Carolina during 2000 and 2001 to evaluate weed control, crop injury, and cotton yield. Weed management systems included different combinations of pyrithiobac preemergence (PRE), fluometuron PRE, CGA-362622 postemergence (POST), pyrithiobac POST, and monosodium salt of methylarsonic acid (MSMA) plus prometryn applied late POST-directed (LAYBY). At Goldsboro in 2000, cotton was injured 74 to 78% by CGA-362622 POST when evaluated 4 to 7 d after treatment (DAT). Injury at Clayton, Goldsboro, and Lewiston in 2001 and Rocky Mount in 2000 was less than 16% 4 to 7 DAT with the same treatment and was not apparent by 62 DAT. CGA-362622 controlled common lambsquarters, common ragweed, Palmer amaranth, sicklepod, smooth pigweed, and Ipomoea species including entireleaf, ivyleaf, and pitted morningglory, and the addition of pyrithiobac to the herbicide system, either PRE or POST, increased control of Amaranthus species, jimsonweed, and prickly sida. CGA-362622 did not control jimsonweed or prickly sida. Fluometuron PRE, pyrithiobac PRE, and MSMA plus prometryn LAYBY were beneficial for increasing weed control and cotton lint yields. Prometryn plus MSMA LAYBY increased control of common ragweed, entireleaf morningglory, jimsonweed, pitted morningglory, and smooth pigweed and provided higher cotton yields than similar systems without a LAYBY. The greatest weed control and greatest cotton lint yields required complete weed management systems that included a combination of PRE, POST, and LAYBY treatments.