Abnormal leaf fall disease caused by Phytophthora meadii leads to significant reduction in the latex production of Hevea brasiliensis, the source of natural rubber. A systematic understanding of this phytopathosystem has not been possible owing to lack of genome or proteome information. In the present study, a comparative transcriptome analysis of Phytophthora resistant (FX 516) and susceptible (RRIM 600) clone of H. brasiliensis after challenge inoculation with P. meadii, the major pathogen affecting rubber was carried out. Attempt was made to understand the major genes involved in the Hevea-Phytophthora interaction and thereby predict a possible defense signaling network in H. brasiliensis. Differential gene expression analysis identified that 9340 genes were upregulated in Phytophthora challenged resistant clone FX 516 when compared with the Phytophthora challenged susceptible clone RRIM 600 and total of 8042 genes were found to be downregulated. Transcript levelsfor many stress receptors, stress responsive genes,kinases, PR proteins, transcription factors, genes involved in various metabolic processes and genes involved in biosynthesis of secondary metabolites were found to be upregulated in challenged FX 516 as compared to the challenged RRIM 600 in transcriptome data analysis. Our results postulate the P. meadii resistance is by predominantly modulating the salicylic acid acid and phenylpropanoid pathways. Functional analyses of candidate genes identified in this study will improve our understanding of resistance mechanisms and will pave way to the development of efficient disease management strategies.