Inspiratory resistive breathing increases plasma cytokines, yet the stimulus (or stimuli) and source(s) remain unknown. We tested the role of reactive oxygen species as stimuli and of monocytes as sources of resistive breathing-induced cytokines. Six healthy subjects performed two resistive breathing sessions at 75% of maximum inspiratory pressure before and after a combination of antioxidants (vitamin E 200 mg, vitamin A 50,000 IU, and vitamin C 1,000 mg per day for 60 days, allopurinol 600 mg/day for 15 days, and N-acetylcysteine 2 g/day for 3 days before the second session). Blood was drawn before, at the end, and at 30 and 120 minutes after resistive breathing. Before antioxidants, plasma cytokine levels (determined by enzyme-linked immunosorbent assay) increased secondary to resistive breathing (tumor necrosis factor-alpha and interleukin [IL]-6 by twofold and IL-1beta by threefold). After antioxidants, plasma IL-1beta became undetectable. The tumor necrosis factor-alpha response to resistive breathing was abolished, and the IL-6 response was significantly blunted. Intracellular cytokine detection (by flow cytometry) showed no change in either the percentage of monocytes producing the cytokines or their mean fluorescence intensity both before and after antioxidants. We conclude that oxidative stress is a major stimulus for the resistive breathing-induced cytokine production and that monocytes play no role in this process.