The purpose of this study was to investigate the association of autonomic nervous system dysregulation with blood pressure variability. Among the 2370 participants in the X-CELLENT study, 577 patients (59.0±10.2 years) were randomly selected to participate in an ancillary ambulatory blood-pressure monitoring study. We proposed a novel autonomic nervous system regulation index termed dSBP/dHR, which was defined as the steepness of the slope of the relationship between the 24-h systolic blood pressure (SBP) and the heart rate (HR) for each participant. Within-subjects s.d. of SBP, weighted for the time interval between consecutive validated readings from 24-h ambulatory blood pressure monitoring, was used to evaluate blood pressure variability. When dSBP/dHR was divided into tertiles, we observed a progressive increase from tertile 1 to tertile 3 in the daytime SBP, a progressive decrease in nighttime SBP, and consequently a progressive increase in the day-night SBP gradient (P<0.001). The s.d. of both daytime and nighttime SBPs were consistently and significantly increased from tertile 1 to tertile 3 (P<0.01). Both before and after adjustment for age, gender and 24-h mean blood pressure, all of these increasing and decreasing trends reached statistical significance (P<0.01). Furthermore, in our sensitivity analysis, when men and women were considered separately, the findings remained unaltered. In summary, autonomic nervous system dysfunction was associated with a heightened day-night SBP gradient and more variable SBP over 24 h in patients with essential hypertension.