Acyrthosiphon pisum (pea aphid) is considered to be one of the most agronomically damaging pests on pea and alfalfa crops, and is responsible for significant yield losses in agriculture. For the efficient control of the parasite, a better understanding of its interaction and associated resistance mechanisms at the molecular level is required. We used two-dimensional gel electrophoresis (2DE) coupled to mass spectrometry (MSMS) analysis to compare the leaf proteome of two pea accessions displaying different phenotypes to A. pisum infestation. Multivariate statistical analysis identified 203 differential proteins under the experimental conditions, 81 of which were identified using a combination of peptide mass fingerprinting (PMF) and MSMS fragmentation. Most of the identified proteins corresponded to amino acid and carbohydrate metabolism, photosynthesis, folding/degradation, stress response, signal transduction and transcription/ translation. Results suggested the involvement of different metabolic pathways that may be activated in order to overcome pea aphid attack in the resistant accession (P665): reduction of photosynthesis and amino acid biosynthesis that may be helpful in tackling pea aphid attack by limiting access to nutrients, up-accumulation of wound signal molecules such as LOXs and LAPs, and activation of the antioxidant ASC-GSH cycle. In contrast, the susceptible accession (cv. Messire) showed an increase in primary metabolism pathways (especially amino acid biosynthesis), from which a relationship to the successful performance of aphids on this accession could be inferred. Results are also discussed with regard to differences in management of photoassimilates against the strong sinks produced by aphid feeding.