Plasmopara viticola is the causal agent of grapevine downy mildew (DM). DM resistant varieties deploy effector-triggered immunity (ETI) to inhibit pathogen growth, which is activated by major resistance loci, the most common of which are Rpv3 and Rpv12. We previously showed that a quick metabolome response lies behind the eti conferred by Rpv3 tiR-nB-LRR genes. Here we used a grape variety operating Rpv12-mediated eti, which is conferred by an independent locus containing cc-nB-LRR genes, to investigate the defence response using Gc/MS, UpLc, UHpLc and RnA-Seq analyses. Eighty-eight metabolites showed significantly different concentration and 432 genes showed differential expression between inoculated resistant leaves and controls. Most metabolite changes in sugars, fatty acids and phenols were similar in timing and direction to those observed in Rpv3-mediated eti but some of them were stronger or more persistent. Activators, elicitors and signal transducers for the formation of reactive oxygen species were early observed in samples undergoing Rpv12-mediated eti and were paralleled and followed by the upregulation of genes belonging to ontology categories associated with salicylic acid signalling, signal transduction, WRKY transcription factors and synthesis of PR-1, PR-2, PR-5 pathogenesis-related proteins. Downy mildew is one of the most destructive diseases of the grapevine, causing significant limitations on grape production in the absence of chemical protection of vineyards. Downy mildew is caused by the biotrophic oomycete Plasmopara viticola (Berk. And Curt) Berl. and Toni, which is native to North America and was introduced into Europe at the end of the nineteenth century. The European bunch grape (Vitis vinifera L.) does not normally activate the immune system in response to P. viticola with a few exceptions 1,2. The introgression of resistant genes from other grape species (i.e. V. rupestris, V. amurensis, V. cinerea, V. riparia and Muscadinia rotundifolia) into the crop germplasm can alleviate the dependence of viticulture on the use of fungicides 3. The pathogen can cause serious damage to any green organ of the grapevine. P. viticola deploys a specialized structure called haustorium to establish a close interaction with grapevines and to leak nutrients from viable host cells 4,5. P. viticola can feed on both susceptible and resistant grapevines and complete its life cycle on both hosts. Resistant grapevines are, however, able to detect the invading pathogen and operate defence responses. The initial phases of the infection are similar on both hosts, but mycelial growth is restricted in resistant hosts and sporangia are released at lower rates than in susceptible hosts. The similarity during early phases of infection suggests the presence of post-infection mechanisms of resistance, including callose deposition, cell wall-associated