Trifludimoxazin, a new protoporphyrinogen oxidase–inhibiting herbicide, is being evaluated for possible use as a soil-residual active herbicide treatment in cotton for control of small-seeded annual broadleaf weeds. Laboratory and greenhouse studies were conducted to compare vertical mobility and cotton tolerance of trifludimoxazin to flumioxazin and saflufenacil, which are two currently registered protoporphyrinogen oxidase–inhibiting herbicides for use in cotton, in three West Texas soils. Vertical soil mobility of trifludimoxazin was similar to flumioxazin in Acuff loam and Olton loam soils, but was more mobile than flumioxazin in the Amarillo loamy sand soil. The depth of trifludimoxazin movement after a 2.5-cm irrigation event ranged from 2.5 to 5.0 cm in all soils, which would not allow for crop selectivity based on herbicide placement, because ideal cotton seeding depth is from 0.6 to 2.54 cm deep. Greenhouse studies indicated that PRE treatments were more injurious than the 14 d preplant treatment when summarized across soils for the three herbicides (43% and 14% injury, respectively). No differences in visual cotton response or dry weight was observed after trifludimoxazin preplant as compared with the nontreated control within each of the three West Texas soils and was similar to the flumioxazin preplant across soils. On the basis of these results, a use pattern for trifludimoxazin in cotton may be established with the use of a more than 14-d preplant restriction before cotton planting.