Scope:Low paraoxonase (PON)1 activities, and high PON1 and low PON3 protein levels arecharacteristic of cardiovascular disease. Our aim was to assess short- and long-term effects ofvirgin olive oils (VOO), enriched with their own phenolic compounds (PC; FVOO) or with themplus complementary PC from thyme (FVOOT), on PON-related variables and the mechanismsinvolved.Methods and results:Two randomized, controlled, double-blind, and crossover interventionswere conducted. In an acute intake study, participants ingested three FVOOs differing in PCcontent. In a sustained intake study, participants ingested a control VOO and two differentFVOOs with the same PC content but differing in PC source. Acute and sustained intake ofVOO and FVOO decreased PON1 protein and increased PON1-associated specific activities,while FVOOT yielded opposite results. PON3 protein levels increased only after sustainedconsumption of VOO. Mechanistic studies performed in rat livers showed that intake of isolatedPC from VOO and from thyme modulate mitogen-activated protein kinases and peroxisomeproliferator-activated receptors regulating PON synthesis, while a combination of these PCscancels such regulation.Conclusion:This study reveals that the intake of phenol-enriched FVOOs modulates oxidativebalance by modifying PON-related variables according to PC content and source, and thismodulation can be perceived as beneficial.