Cardiovascular instability is frequent during hemodialysis. Hypotensive episodes and/or arrhythmias occur in up to 20% of dialyses and sudden death may occur. We followed blood pressure (BP) and pulse rate (PR) changes and occurrence of hypotension, and arrhythmia in 4,458 short frequent dialyses in 23 patients. Regular dialysate (RD) was used for 2,824 dialyses and ultrapure dialysate (UPD) using the Aksys PHD® machine for 1,634 dialyses. Dialysate purity was checked by the limulus test. RD failed European (57%) and USA standards (37%) in 123 samples. UPD passed double the European standard (< 0.125 EU) in all 194 samples. Systolic BP fell 17± 22 mm Hg with RD and 8 ± 20 mm Hg with UPD (p<0.0001) and diastolic BP fell 6± 12 and 2± 16 mm Hg (p<0.0001) respectively. PR increased 2±13 vs. 0± 12 beats/minute (p<0.0001). These changes occurred although ultrafiltration was greater during dialyses with UPD, 1.7 ± 0.9 vs. 1.5 ± 0.8 kg. (p<0.0001). Using either RD or UPD, ultrafiltration correlated with BP and PR changes, but was stronger with UPD. This suggests other factors were at play with RD. Subjectively, patients experienced more BP “crashes” (14% vs. 9%, p<0.0001) and cardiac irregularities (2.0% vs. 0.1%, p<0.0001) with RD than with UPD. Observations were similar whether “tight” cellophane or “open” polysulphone membranes were used, indicating dialysate, not membrane biocompatibility, was the important factor and that the causative factors transferred from dialysate were of low molecular weight. Dialysate impurities are an important factor in cardiovascular instability during hemodialysis.