Background: There is minimal evidence to inform blood flow rate (BFR) during continuous renal replacement therapy (CRRT). Aims: We aimed to assess the effect of BFR on circuit life and solute maintenance during CRRT. Design: A prospective randomised controlled trial. Setting: Twenty-four bed, single-centre, tertiary-level intensive care unit. Participants: Critically ill patients with acute kidney injury treated with CRRT (continuous venovenous haemofiltration [CVVH] or continuous venovenous haemodiafiltration [CVVHDF]). Interventions: Patients were randomised to receive one of two BFRs: 150 mL/min or 250 mL/min. Main outcome measures: The primary outcome was circuit life measured in hours. The secondary outcome was changes in urea and creatinine concentrations (changes from baseline), and delivered treatment for each 12 h period was used to assess solute maintenance. Results: One hundred patients were randomised, with 96 completing the study (150 mL/min, n = 49; 250 mL/min, n = 47) using 462 circuits (245 runs at 150 mL/min and 217 runs at 250 mL/min). Primary outcome: Circuit and patient data were collected until each circuit clotted or was ceased electively for non-clotting reasons. Data for clotted circuits were presented as median (interquartile range [IQR]) and compared using the Mann–Whitney U test. Survival probability for clotted circuits was compared using a log-rank test. Circuit clotting data were analysed for repeated events using hazard ratio (HR). Median circuit life for the first circuit (clotted) was similar for both groups (150 mL/min: 9.1 [5.5, 26] h vs. 10 [4.2, 17] h, p = 0.37). CRRT using a BFR set at 250 mL/min was not more likely to cause clotting compared with 150 mL/min (HR 1.00, 95% CI 0.60–1.69; p = 0.68). Gender, body mass index, weight, vascular access type, length, site, mode of CRRT and international normalised ratio had no effect on clotting risk. CRRT without anticoagulation was more likely to cause clotting compared with use of heparin strategies (HR 1.62, p = 0.003). Longer activated partial thromboplastin time (HR 0.98, p = 0.002] and decreased platelet count (HR 1.19, p = 0.03] were associated with a reduced likelihood of circuit clotting. Secondary outcome: There was a total of 426 12 h periods (150 mL/min, 208; 250 mL/min, 218). Mean hours of treatment per 12 h was 6.3 h (3.7) in the 150 mL/min group and 6.7 h (3.9) in the 250 mL/min group (p = 0.6). There was no difference between the two BFR groups for mean delta urea (−0.06 [SD 0.015] vs. −0.07 [SD 0.01], p = 0.42) or mean delta creatinine (−0.05 [SD 0.01] vs. −0.08 [SD 0.01], p = 0.18). Independent variables associated with less reduction in mean serum urea and creatinine were low haemoglobin level (−0.01 [SD 0.005], p = 0.002; 0.01 [SD 0.005], p = 0.006) and less hours treated (−0.023 [SD 0.001], p = 0.000; −0.02 [SD 0.002], p = 0.001). No effect for body weight was found. Conclusion: There was no difference in circuit life or solute maintenance whether using a BFR of 250 mL/min or 150 mL/min during CRRT.