AbstractToxicological and neurophysiological studies were performed to characterize the resistance mechanism in a cyclodiene‐resistant strain ofDrosophila melanogaster(Maryland strain). Dieldrin had an LC50of 0.058 ppm against the larvae of susceptibleD. melanogaster(Oregon‐R wild type) when formulated in the rearing media. The LC50of the resistant Maryland strain was 10.8 ppm, giving a resistance ratio (LC50‐Maryland/LC50‐susceptible) of 186‐fold. Suction electrode recordings were made from peripheral nerves of the larval central nervous system of test whether reduced nerve sensitivity played any role in the observed resistance. In susceptible preparations (n = 5), inhibition of nerve firing by 1 mM γ‐aminobutyric acid (GABA) was effectively antagonized within 3–10 min by 10 μM dieldrin. In contrast, 30 min incubations with 10 μM dieldrin had no effect on preparations from cyclodiene‐resistant individuals (n = 5). Similarly, 10 μM picrotoxinin blocked GABA‐dependent inhibition in susceptible nerve preparations (n = 3). In recordings from resistant insects (n = 4), picrotoxinin displayed either weak antagonism of GABA or hyperexcitation indistinguishable from susceptible preparations. These results demonstrate that cyclodiene resistance in the Maryland strain ofD. melanogaster(1) is expressed in immature stages, (2) is present at the level of the nerve, and (3) extends to picrotoxinin, albeit at a reduced level compared with dieldrin. The possible role of an altered GABA receptor in this re