Physiological responses to mental tasks and physical exercise were studied independently and combined. We hypothesized that combined mental and physical stresses produce a synergistic interaction. We studied cardiovascular responses to 5 min of static handgrip, mental arithmetic, and the combined stimuli in random order in 12 healthy subjects. Muscle sympathetic nerve activity (SNA) and mean arterial blood pressure (MAP) responses to handgrip and the combined stimuli exceeded responses to mental arithmetic, yet no significant difference existed between responses to handgrip and the combined stimuli. Peak changes in SNA (in %) were greatest during handgrip (188 ± 41), followed by the combined stimuli (166 ± 31) and mental arithmetic (51 ± 9). Peak changes in MAP (in mmHg) were also greatest during handgrip (26 ± 4), followed by the combined stimuli (23 ± 3) and then mental arithmetic (8 ± 2). Peak changes in heart rate (in beats/min) followed the same trend: handgrip (15 ± 2), combined (13 ± 2), and mental arithmetic (10 ± 2). Mental stimulation did not synergistically interact with or add to the responses elicited by handgrip exercise; in fact, a trend existed for math during handgrip to reduce responses relative to handgrip alone.