Two field strains of the Egyptian cotton leafworm Spodoptra littoralis (Lepidoptera: Noctuidae), collected from cotton field in mid and north of Nile River Delta, Egypt, were bioassayed for resistance to some commonly used and a candidate insecticide. Bioassay revealed that the two field strains were both with high resistance to the pyrethroid deltamethrin (RR: 10.1- 14.5 fold), high tolerance to the neonicotinoid acetamiprid (RR: 7.2- 9.1) and moderate level of tolerance to the organophosphate chlorpyrifos and the carbamate methomyl (RR: 4.4 – 6.6 fold); and no resistance to the new chemistry insecticide pyridalyl (RR: 1.8- 1.9). Detoxification enzyme assays revealed that field strains of S. littoralis generally exhibit higher microsomal monooxygenase activity than the laboratory susceptible strain. However, no significant difference in carboxylesterases activity was detected. Baseline activity of acetylcholinesterase (AChE) was established and the laboratory- strain was characterized by the highest activity. Synergism investigations, using the microsomal oxidases inhibitor (Piperonyl butoxide "PBO") and the esterases inhibitor (Triphenyl phosphate "TPP"), proved that the observed levels of resistance in this pest associated with the enhanced activity of Cytochrome P450 monooxygenase. These results lead to the suggestion that rotating of pyridalyl with other insecticides that show low levels of resistance and have different modes of action may be useful for effective control of this pest.