Isometric handgrip exercise (IHG) triggers acute increases in cardiac output to meet the metabolic demands of the active skeletal muscle. An abnormal cardiovascular response to IHG might reflect early stages of cardiovascular disease. In a large community-based cohort, we comprehensively assessed the clinical correlates of acute cardiovascular changes during IHG. In total, 333 randomly recruited subjects (mean age, 53 ± 13 years, 45% women) underwent simultaneous echocardiography and finger applanation tonometry at rest and during 3 min of IHG at 40% maximal handgrip force. We calculated time-domain measures of short-term heart rate variability (HRV) from finger pulse intervals. We assessed the adjusted associations of changes in blood pressure (BP) and echocardiographic indexes with clinical characteristics and HRV measures. During IHG, men presented a stronger absolute increase in heart rate, diastolic BP, left ventricular (LV) volumes and cardiac output than women, even after adjustment for covariables. In adjusted continuous and categorical analyses, age correlated positively with the increase in systolic BP and pulse pressure, but negatively with the increase in LV stroke volume and cardiac output during exercise. After full adjustment, a greater increase in systolic and diastolic BP during exercise was associated with lower absolute real variability (P ≤ 0.026) and root mean square of successive differences (P ≤ 0.032) in pulse intervals at rest. In a general population sample, women presented a weaker cardiovascular response to IHG than men. Older age was associated with greater rise in BP pulsatility and diminished cardiac reserve. Low HRV at rest predicted a higher BP increase during isometric exercise.