Technical Abstract: Increased use of crops genetically modified to produce insecticidal toxins from the bacterium Bacillus thuringiensis (Bt) presents the challenge of designing agricultural systems to manage pests and the evolution of resistance to Bt. We tested whether entomopathogenic nematodes might act synergistically with Bt crops by killing pests in non-Bt refuges and by increasing fitness costs of resistance to Bt. We also tested whether insect mortality and fitness costs were affected by the cotton phytochemical gossypol. The entomopathogenic nematode Steinernema riobrave increased the fitness cost of Bt resistance, indicating that its presence in refuges may slow pest adaptation to Bt crops. No effect on fitness costs was detected for the nematode Heterorhabditis bacteriophora. Gossypol did not alter nematode-imposed fitness costs. Simulation modeling supported the hypothesis that the presence of nematodes in non-Bt refuges may slow resistance evolution. Effects of gossypol on insect mortality from nematodes and nematode reproduction differed between nematode species. Gossypol increased insect mortality caused by H. bacteriophora but did not affect mortality caused by S. riobrave. Gossypol enhanced reproduction of H. bacteriophora and decreased reproduction of S. riobrave. Entomopathogenic nematodes have the potential to act synergistically with Bt crops because they might delay the evolution of resistance to Bt and suppress pest populations in non-Bt refuges.