House flies are major insect pests at dairy farms in Pakistan and are mainly controlled with insecticides of different classes, including organophosphates. To develop a better resistance management strategy, a field strain of house flies was selected in the laboratory to study the potential for the development of resistance, possible mechanisms of resistance and cross-resistance to other insecticides. The selection of the field strain with profenofos for five consecutive generations resulted in the LC₅₀ values to increase from 50.49 to 176.03 µg/ml, and the resistance ratio increased from 29.70 to 103.55 as compared with a laboratory-susceptible strain; however, the resistance was decreased significantly when the selected strain was reared for the next five generations without exposure to any insecticide. The profenofos-selected strain (Profen-SEL) showed cross-resistance to chlorpyrifos and deltamethrin but no cross-resistance observed to spinosad. Synergism studies with piperonyl butoxide and S,S,Stributylphosphorotrithioate indicated that the resistance to profenofos was probably associated with esterase and, possibly, microsomal oxidase activity. Resistance to profenofos in the selected strain suggests that the resistance, owing to instability, could be overcome by switching off profenofos use for few generations in the field or by rotation with different insecticides having different modes of action.