Objective: To evaluate the efficacy and safety of ultrafiltration (UF) combined with haemodialysis (HD) sequential therapy in patients with intradialytic hypotension (IDH) and water retention. Methods: A total of 53 uraemia patients with IDH who could not tolerate dehydration and significant water and sodium retention (net weight gain of more than 4 kg) were randomly divided into control group (28 cases) and treatment group (25 cases). After adjusting dialysis parameters (blood pump speed and excessive filtration), HD was tried again in the control group, and UF combined with HD was given sequential treatment in the treatment group. Outcome measures included efficacy measures (duration of treatment, total water removal, weight loss, dyspnoea score and left ventricular ejection fraction) and safety measures (heart rate, blood pressure, IDH incidence, bleeding and thromboembolic events). Results: In terms of efficacy indicators, In the sequential treatment group, the duration of treatment (740 ± 168 min vs. 380 ± 94 min, p < 0.05), total water removal (5280 ± 968 mL vs. 2980 ± 765 mL, p < 0.05) and the weight loss (2756 ± 537 g vs. 1421 ± 362 g, p < 0.05) was significantly higher than that of control group. Postoperative dyspnoea score (1.92 ± 0.400 vs. 3.32 ± 0.476, p < 0.05), left ventricular ejection fraction (LVEF; 49.25 ± 3.76 vs. 56.46 ± 4.42, p < 0.05) was significantly improved compared with that before treatment, and the difference was statistically significant. In control group, dyspnoea score (1.89 ± 0.416 vs. 1.82 ± 0.390, p > 0.05) and left ventricular ejection fraction (49.04 ± 6.72 vs. 48.61 ± 7.12, p > 0.05) were slightly improved after treatment, but there was no statistical significance. In terms of safety indicators, patients in the control group were prone to significant blood pressure fluctuation during treatment, and the incidence of IDH was significantly higher than that in the treatment group (75% vs. 0%, p < 0.01), the difference was statistically significant, while the other safety indicators (heart rate change, bleeding and thromboembolic events) showed no statistically significant difference between the two groups. Conclusions: Compared with conventional HD, UF combined with HD can safely and effectively reduce water retention in patients with uraemia while avoiding IDH.