The brown planthopper Nilaparvata lugens is one of the most economically important pests of cultivated rice in Southeast Asia. Extensive use of insecticide treatments, such as imidacloprid, fipronil and ethiprole, has resulted in the emergence of multiple resistant strains of N. lugens. Previous investigation of the mechanisms of resistance to imidacloprid and ethiprole demonstrated that overexpression and qualitative changes in the cytochrome P450 gene CYP6ER1 lead to enhanced metabolic detoxification of these compounds. Here, we present the identification of a secondary mechanism enhancing ethiprole resistance mediated by differential splicing and overexpression of CYP419A1, a planthopper-specific, mitochondrial P450 gene. Although metabolic resistance to insecticides is usually mediated by overexpression of P450 genes belonging to either CYP 3 or 4 clades, we validate the protective effect of over-expression of CYP419A1, in vivo, using transgenic Drosophila melanogaster. Additionally, we report some unusual features of both the CYP419A1 gene locus and protein, which include, altered splicing associated with resistance, a non-canonical heme-binding motif and an extreme 5' end extension of the open reading frame. These results provide insight into the molecular mechanisms underpinning resistance to insecticides and have applied implications for the control of a highly damaging crop pest.