European red mite, Panonychus ulmi Koch, is one of the major pests of apple trees in Iran as well as in the world. By feeding on apple parenchymal cells, P. ulmi significantly reduces photosynthesis and disrupts general plant activity, and leads to a significant reduction in the quality and quantity of apple fruits. Regarding the high damage ability of the mite, is often unavoidable its chemical control to prevent crop loss. Spirodiclofen, a specific and non-systemic acaricide, belongs to tetronic acids and acts by inhibiting the effects of acetyl coenzyme-A-carboxylase. One of the importanat problems in the pest chemical control is the resistance development. Resistance is ability heritable in an insect or mite strain to tolerate lethal doses of a pesticide. In order to evaluate P. ulmi resistance to spirodiclofen, several populations of P. ulmi were collected from apple orchards of Iran including: West Azarbaijan (Urmia, Shahin Dezh, Mahabad, Salmas), East Azarbaijan (Miyane, Marand, Maragheh, Ahar) and Isfahan (Semirom). The average lethal doses (LC 50s ) of different populations were measured by bioassay tests using a Potter spray tower. The possible cross resistance between spirodiclofen, spiromesifen (mode of action is similar to spirodiclofen) and etoxazole (a growth inhibitor group with effect on chitin synthase enzyme) were also investigated. The highest resistance to spirodiclofen observed in Urmia and Shahin dezh with resistance ratio 214.5 and 149.4, respectively. Ahar population was the most susceptible population with an LC 50 value of 2.1 (mg a.i./L). Against spiromesifen also Ahar population was the most susceptible (LC 50 value of 0.3 mg a.i./L) and Urmia and Shahin Dezh were the most resistant populations with the resistance ratio 22.2 and 21.7, respectively. It seems that a cross resistance occures between spiromesifen and spirodiclofen. Tested populations showed a different susceptibility to etoxazole, so that, Ahar and Marand were the most susceptible and resistance populations respectively. To elucidate the resistance mechanisms, the role of detoxyfing enzymes (Cytochrome P450 Monoxygenase, esterases and glutathione s transferases) and their activities were determind. Therefor, the effects of pretreatment three synergists, pipronil Botoxide (PBO), triphenilphosphat (TPP) and di ethyl maleat (DEM), were investigated. PBO pretreatment caused higher reduction in the LC 50 values and the synergistic ratios for PBO in the population of Urmia and Shahin dezh were estimated as 2.2 and 3.1. In addition PBO reduced the resistance ratios. Inhibiting esterases and glutathione s transferases with TPP and DEM, respectively, showed that these enzymes have no major low in spirodiclofen resistance. Morever, in vitro enzyme activity measurments, showed a high P450 activity in the resistant populations. In conclusion possibly enhanced detoxification, specially P450 play a major role in spirodiclofen resistance in P. ulmi . The results can be used in the early detection of spirodiclofen resistance in P. ulmi populations and preventing or delaying the resistance development and finally it may help in reducing acaricide applications and environment damages. Keywords: Apple tree, European red mite, P. ulmi , Resistance, Spirodiclofen, Cytochrome P450 Monoxygenase.