Oxidative stress has been implicated as a critical contributor to the pathogenesis of cardiovascular disease. Additionally, catecholamine increases and inflammation are related to increases in oxidative stress. Although, physical and psychological stress elicit elevations in catecholamine release and inflammation, there are no studies examining the combined impact of physical and mental challenge on catecholamine, inflammation, and oxidative stress. PURPOSE: The purpose of this study was to examine the catecholamine (epinephrine [EPI] and norepinephrine [NE]), interleukin-2 (IL-2) and 8-isoprostane responses to a dual stress model (combined physical and mental challenge). To elucidate possible mechanisms, relationships among EPI, NE, IL-2, and 8-isoprostane were also examined. METHODS: Seven participants (VO2max = 45.13 ± 7.70 ml·kg·min-1) completed two experimental conditions. The exercise-alone condition (EAC) consisted of cycling at 60% VO2max for 37 minutes, while the dual-stress condition (DSC) included 20 minutes of a mental challenge while cycling. RESULTS: DSC showed greater EPI and 8-isoprostane levels (significant condition by time interaction). In addition, NE and IL-2 revealed significant increases over time in both conditions. EPI area-under-the-curve (AUC) was positively correlated with NE AUC and IL-2 AUC (r = 0.805 and r = 0.674, p < 0.01, respectively). Additionally, NE AUC was positively correlated with IL-2 AUC and peak 8-isoprostane (r = 0.575 and r = 0.554, p < 0.05, respectively). Finally, peak IL-2 was positively correlated with peak 8-isoprostane (r = 0.577, p < 0.05). CONCLUSION: These results suggest that elevations in catecholamines, IL-2 and oxidative stress in response to physical and mental challenge, may contribute to the pathogenesis of cardiovascular disease. Furthermore, the elevations in NE and IL-2 may explain the elevated oxidative stress during dual stress. Cautious interpretation and further investigation are warranted to understand these results in the context of cardiovascular disease and stress.