Susceptibility to the severe Citrus tristeza virus (CTV), T36, is higher for Citrus macrophylla (CM) than for C. aurantium (CA). How host-virus interactions are reflected in host physiology is largely unknown. In this study, the profile of metabolites and the antioxidant activity in the phloem sap of healthy and infected CA and CM plants were evaluated. The phloem sap of quick decline (T36) and stem pitting (T318A) infected citrus, and control plants was collected by centrifugation, and the enzymes and metabolites analyzed. The activity of the antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), in infected plants increased significantly in CM and decreased in CA, compared to the healthy controls. Using LC-HRMS2 a metabolic profile rich in secondary metabolites was assigned to healthy CA, compared to healthy CM. CTV infection of CA caused a drastic reduction in secondary metabolites, but not in CM. In conclusion, CA and CM have a different response to severe CTV isolates and we propose that the low susceptibility of CA to T36 may be related to the interaction of the virus with the host's metabolism, which reduces significantly the synthesis of flavonoids and antioxidant enzyme activity.