Experiments were executed to provide new evidence relevant to the recent suggestion that fatigue should augment or retard cardiovascular response depending on the difficulty of the challenge at hand. Participants walked on a treadmill while wearing a vest fitted with 5 or 25 pounds of weight. Later, they mounted a recumbent stationary bicycle and were asked to pedal with the chance to earn a modest incentive if they attained a low or high cycling standard (i.e., if they met an easy or difficult cycling challenge). Analysis of CV responses during the cycling period indicated expected interactions for systolic blood pressure and heart rate. Whereas responses were stronger for the Heavy-Vest (i.e., high-fatigue) group when the standard was low, they were weaker for this group when the standard was high. Experiments 2 and 3 evaluated a nonfatigue interpretation of the main results and yielded findings that supported the fatigue interpretation.