We investigated the way dialysate magnesium (dMg) concentrations could affect blood pressure (BP) during hemodialysis (HD). Eight HD patients underwent four midweek HD treatments consecutively, using, during each four-hour HD session, one of the following four dialysate formulations, in randomized order, which differed only with regard to dMg and dialysate calcium (dCa) concentrations (in mmol/L): 0.75 dMg, 1.75 dCa (group I); 0.25 dMg, 1.75 dCa (group II); 0.75 dMg, 1.25 dCa (group III); 0.25 dMg, 1.25 dCa (group IV). Before HD and at four 60-minute intervals during the HD sessions, BP and noninvasive measurements of cardiac index (CI) were obtained. Additionally, 14 HD patients were treated for four weeks with 0.5 mmol/L dMg, followed by four weeks with 0.25 mmol/L dMg, and another four weeks with 0.75 mmol/L dMg, in random order. In all treatments dCa was 1.25 mmol/L. BP and symptoms were recorded during each HD session. Mean arterial pressure (MAP) decreased to a significantly (P < 0.05) greater extent in group IV compared to the other groups. This substantial drop in MAP by 15.2% in group IV, paralleled by a 12.1% and 17% drop in CI and stroke index, respectively, was not seen in group II, despite comparable reductions in intradialytic serum Mg (sMg) of about 35% in both groups. In groups I and III, the increase in sMg by 2% did not compromise BP via vasodilatation. In the second study, treatment with 0.75 mmol/L dMg was superior to the other two treatments regarding intradialytic morbidity (P < 0.001) and BP stability (P < 0.05). We (1) identified a dialysis solution containing 0.25 mmol/L Mg and 1.25 mmol/L Ca as a major cause of intradialytic hypotension (IDH) due to an impairment of myocardial contractility, and (2) showed that increasing dMg level to 0.75 mmol/L could prevent IDH frequently seen with the use of 1.25 mmol/L dCa. Thus, manipulating dMg levels independently or in concert with dCa levels might have important implications with regard to dialysis tolerance.