Quantifying the component-specific contribution to the oxidative potential (OP) of ambient particle matter (PM) is the key information to properly representing its acute health hazards. In this study, we investigated the interactions between the major contributors to OP, i.e., transition metals and quinones, to highlight the relative effects of these species to the total OP. Several synergistic and antagonistic interactions were found that significantly change the redox properties of their binary mixtures, increasing or decreasing the values computed by a simple additive model. Such results from the standard solutions were confirmed by extending the study to atmospheric PM2.5 samples collected in winter in the Lombardia region, a hot spot for air pollution in northern Italy. This work highlights that a solid estimation of oxidative properties of ambient PM requires an interaction-based approach accounting for the interaction effects between metals and quinones.