Insecticide resistance in the southern house mosquito, Culex pipiens quinquefasciatus, is a major obstacle in controlling population densities as well as limiting disease transmission. The two major mechanisms that confer permethrin resistance are insensitivity of the target site (due to a L1014F mutation in the voltage sensitive sodium channel, known as kdr) and cytochrome P450 monooxygenase detoxification (P450). Understanding the resistance contribution of each mechanism as well as the interaction between these mechanisms is important for determining how high levels of resistance and multigenic resistance can evolve in the field. Alone, the P450 mechanism in both the homozygous and heterozygous states confers a higher level of resistance (1,300-fold and 94 to 100-fold, respectively) than kdr alone (homozygote=70-fold and heterozygote=10 to 48-fold). By comparing observed resistance ratios to those expected under the null hypothesis of an additive type interaction, we determined that these two major mechanisms of permethrin resistance interact in a greater than additive fashion when all possible genotype combinations were considered.