Doxorubicin (DOX), an anthracycline used to treat a variety of cancers, is known to generate intracellular reactive oxygen species. Moreover, many patients who have undergone chemotherapy complain of cognitive dysfunction often lasting years after cessation of the chemotherapy. Previously, we reported that intraperitoneal administration of DOX led to elevated TNF-α and oxidative stress in the plasma and brain of mice. However, the mechanisms involved in nontargeted tissue damage remain unknown. In this study, we measured plasma oxidative stress and cytokine levels in patients treated with DOX. We observed increased plasma protein carbonylation and elevation of TNF-α 6 h after DOX administration in the context of multiagent chemotherapy regimens. Importantly, patients not treated coincidentally with 2-mercaptoethane sulfonate (MESNA) showed statistically significantly increased plasma protein-bound 4-hydroxynonenal, whereas those who had been coincidentally treated with MESNA as part of their multiagent chemotherapy regimen did not, suggesting that concomitant administration of the antioxidant MESNA with DOX prevents intravascular oxidative stress. We demonstrate in a murine model that MESNA suppressed DOX-induced increased plasma oxidative stress indexed by protein carbonyls and protein-bound HNE, and also suppressed DOX-induced increased peripheral TNF-α levels. A direct interaction between DOX and MESNA was demonstrated by MESNA suppression of DOX-induced DCF fluorescence. Using redox proteomics, we identified apolipoprotein A1 (APOA1) in both patients and mice after DOX administration as having increased specific carbonyl levels. Macrophage stimulation studies showed that oxidized APOA1 increased TNF-α levels and augmented TNF-α release by lipopolysaccharide, effects that were prevented by MESNA. This study is the first to demonstrate that DOX oxidizes plasma APOA1, that oxidized APOA1 enhances macrophage TNF-α release and thus could contribute to potential subsequent TNF-α-mediated toxicity, and that MESNA interacts with DOX to block this mechanism and suggests that MESNA could reduce systemic side effects of DOX.