Broadleaf weed control is needed to optimize cotton (Gossypium hirsutum L.) yield. Pyrithiobac controls many broadleaf weeds in cotton when applied preemergence or postemergence. Research was conducted to determine if cultivar selection and early-season irrigation influenced cotton response to pyrithiobac at 70 or 140 g ai ha-1 applied postemergence or 70 g ha-1 applied preemergence followed by 70 g ha-1 applied postemergence. Injury was greater when pyrithiobac was applied postemergence over-thetop at 140 g ha-1 than at 70 g ha-1, irrespective of cultivar. For most cultivars, pyrithiobac at 140 g ha-1 postemergence over-the-top was more injurious than when applied preemergence at 70 g ha-1 followed by pyrithiobac at 70 g ha-1 postemergence over-the-top. Cotton was injured more when pyrithiobac was applied 1 d following 4 cm of irrigation than when this irrigation treatment was not applied, regardless of pyrithiobac rate. Although some differences in seed cotton yield were noted among pyrithiobac treatments, cultivar selection and early-season irrigation did not affect seed cotton yield.