Using acetate as a buffer during hemodialysis is recognized to predispose to intradialytic hypotension; however, bicarbonate-based dialysis is not acetate free. Paired hemodiafiltration (PHF) is a novel online acetate-free technique. We investigated whether PHF is capable of abrogating the changes in systemic hemodynamics and troponin T (cTnT) seen with conventional hemodialysis. Twelve patients entered a randomized crossover study. Blood pressure (BP) and a full range of hemodynamic variables were measured throughout PHF and standard dialysis using continuous pulse wave analysis. We also measured predialysis cTnT in 54 stable and unstable dialysis patients. BP was lower during PHF but without increased instability. Stoke volume and cardiac output declined progressively during both treatments but to a much lesser extent during PHF (p = 0.003, p < 0.0001 respectively), whereas peripheral resistance rose to a larger degree during hemodialysis (p < 0.0001). cTnT levels were lower before PHF as compared with hemodialysis (p = 0.023), with levels falling after PHF and rising after hemodialysis (p < 0.0001). In the supplementary patient group, predialysis median serum cTnT was higher in the unstable patients (p = 0.0001). This study demonstrates that PHF (without exposure to acetate) is associated with less deterioration in systemic hemodynamics, maintenance of BP, and less suppression of myocardial contractility as compared with bicarbonate dialysis.