Cardiac resynchronization therapy (CRT) improves cardiac hemodynamics. Therefore, the maintenance dose of loop diuretic therapy might be reduced. Consecutive patients who underwent CRT (n = 648) were retrospectively evaluated. Loop diuretic dose was recorded at baseline before implantation and 6 months later with patients classified into 4 groups: (1) no loop diuretic, (2) down-titration, (3) unchanged dose, and (4) up-titration. Afterward total loop diuretic exposure was calculated. Renal function trajectories were evaluated as the difference between implantation and censoring serum creatinine (Cr) value. Clinical outcome was evaluated as the combined end point of heart failure readmissions and all-cause mortality. Independent predictors of successful loop diuretic down-titration were identified. Two hundred ninety-six patients (46%) received no loop diuretic at follow-up, 126 (19%) underwent down-titration, 137 (21%) remained on a stable dose, and 89 (14%) underwent up-titration. In comparison with the group that was free from loop diuretics (Cr = +0.06 mg/dl), renal function deteriorated faster during follow-up in patients on stable doses (Cr = +0.29 mg/dl; p = 0.045) and those underwent up-titration (Cr = +0.44 mg/dl; p = 0.009) but not in patients who were down-titrated (Cr = +0.13 mg/dl; p = 1.00). Patients receiving down-titration had a lower risk for the combined clinical end point (adjusted hazards ratio 0.43; confidence interval 0.22 to 0.83; p = 0.012). Factors associated with successful down-titration after 6 months of CRT included nonischemic cardiomyopathy, higher baseline dose of diuretics, higher ejection fraction at 6 weeks, and lower right ventricular systolic pressure at 6 weeks. In conclusion, after CRT, down-titration of loop diuretics is often feasible and associated with improved outcome and a slower rate of kidney function decline. Patients with nonischemic cardiomyopathy, treated with high doses of loop diuretics before implantation and beneficial left ventricular remodeling with CRT, are most likely to tolerate loop diuretic down-titration.