Background: The cause of blood pressure (BP) changes during uncomplicated hemodialysis (HD) has not been fully investigated. Controversy exists whether changes in BP result from changes in stroke volume (SV) or total peripheral resistance (TPR). Methods: We investigated 19 patients using continuous BP monitoring (Portapres<sup>®</sup>) and subsequent Modelflow<sup>®</sup> analysis, yielding continuous SV, cardiac output (CO) and TPR values. Blood volume (BV) monitoring was also performed. For each patient, the sensitivity index (SI) was calculated. The SI is the slope of the curve depicting the relationship between the systolic BP (SBP) response and the BV response. The patients were divided into two groups: group A had an SI >1 which means a decrease in SBP in response to BV change, and group B had an SI <1. In these patients, SBP remained stable despite a BV change. Results: Baseline characteristics and baseline values of all parameters were similar between the groups. In group A, SBP decreased by 25 ± 19 mm Hg and in group B the SBP increased by 5.0 ± 29 mm Hg (p < 0.05), while BV change was similar (10.6 ± 4.9 and 11.2 ± 4.2%, respectively). The difference in SBP response was caused by a different SV response (group A –44 ± 16% and group B –26 ± 18%, p = 0.04), while the TPR response was similar (71 ± 27% in group A vs. 59 ± 58% in group B). Conclusion: Patients responding with a BP decrease to BV reduction during uncomplicated HD differ in their SV response from patients with a stable BP.