Mental stress consistently increases heart rate (HR) and blood pressure (BP) in humans, despite inconsistent sympathetic neural responses that include increases, decreases, or no change in muscle sympathetic nerve activity (MSNA). The purpose of the present study was to examine associations between MSNA, BP, and HR responses to mental stress. Leg MSNA, BP, HR, and perceived stress levels were recorded during 3-5 min of mental arithmetic in 82 subjects (53 men and 29 women). Subjects were divided into positive responders (3 bursts/min; n=40), negative responders (-3 bursts/min; n=9), and nonresponders (n=33). Mental stress increased MSNA in positive responders (6±1 bursts/min), decreased MSNA in negative responders (-6±1 bursts/min), and did not change MSNA in nonresponders (1±1 bursts/min). Mental stress increased mean BP and HR similarly in positive responders (15±1 mmHg and 16±1 beats/min; P<0.001), nonresponders (15±1 mmHg and 19±2 beats/min; P<0.001), and negative responders (12±2 mmHg and 19±3 beats/min; P<0.001). Perceived stress levels and sex distributions were similar across responders and nonresponders; thus perceived stress and sex do not appear to influence MSNA during mental stress. However, men demonstrated higher increases of mean BP during mental stress when compared to women (16±1 mmHg vs. 12±1 mmHg; P<0.05), despite no differences in MSNA responses. In conclusion, our results demonstrate marked differences in MSNA responses to mental stress and a disassociation between MSNA and BP responses to mental stress, suggesting complex patterns of vascular responsiveness during mental stress.