Myzus persicae, commonly known as green peach aphid (GPA), is a sap-sucking insect with a broad host range. Arabidopsis thaliana responds to GPA infestation with elevated expression of the PHYTOALEXIN DEFICIENT4 (PAD4) gene. Previously, we had demonstrated that the loss of PAD4 gene function compromises Arabidopsis resistance to GPA. In contrast, a mutation in the Arabidopsis SUPPRESSOR OF SALICYLIC ACID INSENSITIVITY2 (SSI2) gene, which encodes a desaturase involved in lipid metabolism, resulted in hyper-resistance to GPA. We demonstrate here that PAD4 is required for the ssi2-dependent heightened resistance to GPA. Based on electrical monitoring of insect behavior and bioassays in which the insect was given a choice between the wild type and the ssi2 mutant, it is concluded that the ssi2-conferred resistance is not due to deterrence of insect settling or feeding from the phloem of the mutant. Instead, hyper-resistance in the ssi2 mutant results from heightened antibiosis that curtails insect reproduction. Petiole exudates collected from uninfested ssi2 plants contain elevated levels of an activity that interferes with aphid reproduction in synthetic diets. PAD4 was required for the accumulation of this antibiotic activity in petiole exudates, supporting the role of PAD4 in phloem-based resistance. Because PAD4 expression is not elevated in the ssi2 mutant, we suggest that basal PAD4 expression contributes to this antibiosis.