Cotton, Gossypium hirsutum L, plants expressing Cry1Ac and Cry1F (Phytogen 440W) insecticidal crystal proteins of Bacillus thuringiensis (Bt) Berliner, were evaluated against natural populations of tobacco budworm, Heliothis virescens (F.), and bollworm, Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae), across 13 southern U.S. locations that sustained low, moderate, and high infestations. The intrinsic activity of Phytogen 440W was compared with nontreated non-Bt cotton (PSC355) and with management strategies in which supplemental insecticides targeting heliothines were applied to Phytogen 440W and to PSC355 cotton. Infestations were composed primarily of bollworm, which is the least sensitive of the heliothine complex to Cry toxins. Therefore, damage recorded in these studies was primarily due to bollworm. Greater than 75% of all test sites sustained heliothine infestations categorized as moderate to high (10.6–64.0% peak damaged bolls in nontreated PSC355). Phytogen 440W, alone or managed with supplemental insecticide applications, reduced heliothine-damaged plant terminals, squares (flower buds), flowers, and bolls equal to or better (1.0–79.0-fold) than managing a non-Bt cotton variety with foliar insecticides across all infestation environments. Rarely (frequency of ≤11% averaged across structures), sprayed Phytogen 440W reduced damaged structures compared with nontreated Phytogen 440W. Protection against heliothine-induced plant damage was similar across the three levels of infestation for each viable management strategy, with exception to damaged squares for nontreated Phytogen 440W. In situations of moderate to high heliothine infestations, cotton plants expressing Cry1Ac and Cry1F may sustain higher levels of damage compared with that same variety in low infestations. No significant difference in yield was observed among heliothine management strategies within each infestation level, indicating cotton plants may compensate for those levels of plant damage. These findings indicate Phytogen 440W containing Cry1Ac and Cry1F provided consistent control of heliothines across a range of environments and infestation levels.