Cotton, Gossypium hirsutum (L.), is an economically important crop in the United States that is plagued by a complex of insect pests. Two key pests of cotton in the midsouthern United States are the tarnished plant bug, Lygus lineolaris (Palisot de Beauvois) (Hemiptera: Miridae), and bollworm, Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae). A suite of highly effective synthetic insecticides is typically used for control of these pests. However, it is unclear how the combined management of these two insect pests with biological insecticides impacts the economics of cotton production. To address this shortcoming, we conducted a field experiment in the Mississippi Delta over 2 yr to study the effects of synthetic and biological insecticides for control of the tarnished plant bug and bollworm on cotton yield. The results indicated the control of tarnished plant bug with synthetic insecticides had the most significant impact on cotton yield and net returns. The conventional tarnished plant bug treatment also significantly increased bollworm density and damage, but these increases did not significantly alter yield or net return in non–Bacillus thuringiensis (Bt) or Bt cottons. The economic benefit of a conventional approach to tarnished plant bug control with synthetic insecticides was US$438.07/ha in non-Bt and $700.88/ha in Bt cotton relative to those treated with a biological insecticide. The biological insecticides used for this study were ineffective at significantly altering yield or net return. However, for insect management in cotton to be sustainable, alternatives must be found to complement conventional synthetic insecticides.