Background <p>We assessed whether oral acetazolamide (ACZ) increases diuresis and reduces chloride loss when given alongside high-dose intravenous (IV) furosemide in patients admitted to hospital with HF.</p> Methods and Results <p>ADA-HF was a single-centre, open-label, randomised controlled trial. Patients were randomised to ACZ 250&#xa0;mg twice daily plus high-dose (240&#xa0;mg per day) IV furosemide infusion (standard of care (SoC)) versus SoC alone for 4&#xa0;days. The co-primary endpoints were (1) daily net fluid loss between baseline and day 4 and (2) change in serum chloride level from baseline to day 4. A total of 46 patients (median age, 76; 65% male; median N-terminal pro-B-type natriuretic peptide, 4097&#xa0;ng/L) from a screened population of 207 were randomised (23 to ACZ, 23 to SoC). The median daily net fluid loss was 1073&#xa0;mL (1st–3rd quartile range 682–1419&#xa0;mL) in the ACZ arm vs. 1029&#xa0;mL (201–1432&#xa0;mL) in the SoC arm (<i>P</i> = 0.51). There was no change in serum chloride concentration in the ACZ arm, whereas chloride fell by 7 (2–10) mmol/L in the SoC arm (<i>P</i> &lt; 0.001). The number of adverse and serious adverse events ((S)AE) was numerically greater in the ACZ arm (51 events in 16 patients vs. 29 events in 10 patients, <i>P</i> = 0.24). Overall, 8 patients (30%) experienced (S)AEs possibly related to ACZ, and two of whom withdrew from the trial.</p> Conclusions <p>Acetazolamide has a significant “chloride-sparing” effect in patients given high-dose IV furosemide. However, ACZ did not significantly increase diuresis, and side effects from oral ACZ were frequent.</p> Trial registration. <p>ISRCTN13060336; 9/2/2023.</p> Graphical Abstract <p><b>A</b> change in fluid balance and <b>B</b> change in serum chloride; HF, heart failure; ACZ, acetazolamide; SoC, standard of care; RCT, randomised controlled trial; NT-pro-BNP, N-terminal pro-B-type natriuretic peptide</p> <p></p>