There have been no reports evaluating the impact of long-acting loop diuretics (LLD) on the outcome of heart failure (HF) and arrhythmia treatment in HF with reduced ejection fraction (HFrEF) patients implanted with a cardiac resynchronization therapy (CRT) device.This was a prospective, single-blind, randomized crossover study. We allocated 21 consecutive CRT implanted patients into 2 groups. The furosemide group received furosemide as a first treatment and azosemide as a second treatment. The azosemide group received this treatment in the reverse order. The first treatment was given to each group for 6 months and the second treatment continued for an additional 6 months. We combined the data of each medication regimen in each group and analyzed it at baseline, 6 months, and 1 year. The primary endpoints were the variation of fluid index and thoracic impedance measured by CRT at 6 months.The baseline characteristics were similar for both groups. The difference in the primary endpoints was not statistically significant between the 2 medication arms (fluid index: -29.6 ± 64.4 versus 16.2 ± 48.2; P = 0.22, thoracic impedance: -0.49 ± 17.8 versus 2.45 ± 12.5; P = 0.56). Likewise, the clinical outcome of HF and the CRT derived parameters in both arms were comparable.HFrEF patients taking LLD after CRT implantation might be comparable to those taking short-acting loop diuretics in the treatment of HF and HF-associated arrhythmias.