The European red mite, Panonychus ulmi Koch, is one of the most important pests in apple orchards of Iran as well as the world. Fenpyroximate is one of the most common acaricide, which has been extensively used against this pest . The Mitochondrial Electron Traort Inhibitors (METI’s) at complex I has been the well-known target site of fenpyroximate. To evaluate fenpyroximate resistance in field-collected populations of P. ulmi , 11 populations were collected from commercial apple orchards of East Azarbaijan, West Azarbaijan, and Isfahan provinces. and one population of Belgium. The fenpyroximate toxicity was determined using a Potter spray tower. The LC 50 values ranged from 121.8 to 5713.9. mg a.i. L -1 . Orumih population was found as the susceptible and padena-deverajan was detected as the most resistant population respectively. Synergistic assays using Piperonyl butoxide (PBO), a cytochrome P450 monooxygenase inhibitor, significantly increased fenpyroximate toxicity in the PSR-TK population which a synergistic ratio (SR) of 6.72-fold. Also, pretreatment with triphenylphosphate (TPP) resulted in reduced LC 50 values of fenpyroximate in Shahin Dej (SR = 6.07-fold) and PSR-TK (SR= 2.68-fold) populations. Cross resistance assay was performed using PSR-TK and Shahin Dej populations against pyridaben and cyflumetofen and the results suggested that fenpyroximate resistant populations are also resistant to pyridaben . In addition to synergism assays, to determine the role of detoxification enzymes in resistance development, the activities of these enzymes were also evaluated. The esterase activity was estimated 2.24-fold higher in the resistant population of Shahin Dej. Furthermore, the activity of glutathione S-transferases (GSTs), in the Shahin Dej population showed 1.15-fold higher activity in susceptible populations and activity P450s were revealed significant differences between population resistant and susceptible . A T (subunit of complex I ) fragment harboring two previously known mutations H92R and A94V which have been linked to METI-I resistance was amplified and sequenced Furthermore, a PCR-RFLP assay using enzyme TseI was used to determine the frequency of A94V mutation. The results of both sequencing and PCR-RFLP showed that none of the mutations are possibly involved in fenpyroximate resistance in tested populations. Overall, in the present study, relatively moderate to high levels of resistance to fenpyroximate were found in P. ulmi populations and the resistance could be related to the enhanced detoxification. The result provides useful information in the early detection and management of fenpyroximate resistance in P. ulmi. Key Words: Fenpyroximate , Detoxification Enzymes, Target site mutations , METI-I .