The present study examined the effects of acute exercise on anxiogenic responding to 65% O(2)/35% CO(2) challenge. Participants (N=92) were 51 female and 41 male volunteers ranging in age from 17 to 24 (M=19.43, SD=1.31). Participants had no history of panic attacks and were randomized to moderate treadmill exercise (i.e., 70% of HR(max)) or quiet rest prior to taking a single vital capacity inhalation of 35% CO(2)/65% O(2). Gender and measures of negative affectivity and anxiety sensitivity were included in the design as control variables. Results indicated participants who exercised prior to challenge showed significantly reduced reactivity compared to their counterparts who rested prior to challenge. Importantly, the effect sizes for the advantage of exercise over rest remained in the medium to large range (i.e., partial eta(2)>.07) after controlling for the effects of gender, anxiety sensitivity, and negative affectivity. These findings are the first to demonstrate that the anti-panic effects of exercise are unique from, and cannot be better explained by, established risk factors of CO(2) challenge reactivity.