The toxicity of fenitrothion and fenitrothion plus synergists was determined by topical application to adults of fenitrothion‐resistant (571ab) and ‐susceptible (Cooper) strains of Musca domestica L. The strain 571ab was 232‐fold resistant to fenitrothion when compared with the Cooper strain. Co‐administration of fenitrothion with three synergists, namely piperonyl butoxide (PBO), tributylphosphorotrithioate (DEF) and diethyl maleate (DEM) was investigated, respectively, at 1 : 5, 1 : 5 and 1 : 10 ratio. This co‐administration of fenitrothion with PBO, DEF and DEM caused a decrease in the doses which produced 50% lethality (LD50s) in 571ab but had no synergistic effect on fenitrothion toxicity was observed in the Cooper strain. The effect of topical application of fenitrothion alone and in combination with PBO, DEF and DEM at the LD50 level on some enzyme activities in 571ab and Cooper strains was examined. The application of fenitrothion alone and in combination with DEF and DEM at LD50 level caused a significant decrease in activities of total esterases, acetylcholinesterase (AChE) and glutathione S‐transferase (GST) in the 571ab strain. The decrease in GST activity was not significant in treated flies of the Cooper strain when compared with GST activity of control flies. A non‐significant effect on total cytochrome P450 level was observed with fenitrothion alone and the fenitrothion + PBO treatment. No increase in activity level of total esterases, AChE and GST was found, which might suggest that changes in activity level of these enzymes are not related to fenitrothion resistance in the 571ab strain.