Purpose <p>This study aimed to compare a high (HBF) and low (LBF) bicarbonate (HCO₃⁻) replacement fluid over 96&#xa0;h after continuous veno-venous hemofiltration (CVVH) initiation using regional citrate anticoagulation to determine which fluid achieved better acid–base balance.</p> Methods <p>In this prospective, randomized, controlled, open-label, cross-over, single-center trial, patients were randomized to initially receive either LBF (22&#xa0;mmol/l HCO₃⁻) or HBF (30&#xa0;mmol/l HCO₃⁻) for 48&#xa0;h (first phase), followed by changing to the other fluid for a further 48&#xa0;h (second phase). Intracorporeal pH and HCO₃⁻ changes were analyzed by calculating the rates of levels outside the standard values (excursion rates). Generalized estimating equations were performed to estimate the odds ratios for at least one pH/HCO₃⁻ excursion. Time to normalization within the first phase for pH and HCO₃⁻ was assessed using Kaplan–Meier curves and log-rank tests.</p> Results <p>A total of 88 patients were included. The rates for at least one pH and HCO₃⁻ excursion were higher in patients treated with HBF compared to LBF (pH: first phase 52% vs. 41%; second phase 48% vs. 34%; HCO₃⁻: first phase 68% vs. 43%; second phase 73% vs. 43%). Adjusted odds ratios were 1.78 (95% CI 1.12–2.82; <i>p</i> = 0.015) for pH and 3.60 (95% CI 2.16–5.99; <i>p</i> &lt; 0.001) for HCO₃⁻. The time to normalization of pH in acidotic patients and of HCO₃⁻ in patients with low HCO₃⁻ did not differ significantly between HBF and LBF (<i>p</i> = 0.102, <i>p</i> = 0.468).</p> Conclusion <p>LBF showed significantly lower rates of pH and HCO₃⁻ excursions compared to HBF and no significant differences to the pH normalization in acidotic patients were observed.</p> ClinicalTrials.gov-identifier <p>NCT04071171.</p>