Recommendations on Cardiac Resynchronization Therapy (CRT) in patients with atrial fibrillation or flutter (AF) are based on less robust evidence than those in sinus rhythm. We aimed to assess the efficacy of CRT upgrade in the BUDAPEST-CRT Upgrade trial population by their baseline rhythm. Heart Failure patients with reduced ejection fraction (HFrEF) and priorly implanted pacemaker (PM) or implantable cardioverter defibrillator (ICD) and ≥20% right ventricular (RV) pacing burden were randomized to CRT-D upgrade (n=215) or ICD (n=145). Primary- [HF hospitalization (HFH), all-cause mortality, or <15% reduction of left ventricular end-systolic volume] and secondary outcomes were investigated. At enrolment 131 (36%) patients had AF, who had an increased risk for HFH as compared to those with sinus rhythm (SR) [adjusted hazard ratio (aHR) 2.99; 95%CI 1.26-7.13; P=0.013]. The effect of CRT-D upgrade was similar in patients with AF as in those with SR [AF adjusted odds ratio (aOR) 0.06; 95%CI 0.02 to 0.17; P‹0.001; SR aOR 0.13; 95%CI 0.07 to 0.27; P‹0.001; interaction P=0.29] during the mean follow-up time of 12.4 months. Also it decreased the risk of HFH or all-cause mortality (aHR 0.33; 95%CI 0.16 to 0.70; P=0.003; interaction P=0.17) and improved the echocardiographic response (left ventricular end-diastolic volume difference -49.21mL; 95%CI -69.10 to -29.32; P‹0.001; interaction P=0.21). In HFrEF patients with AF and PM/ICD with high RV pacing burden, CRT-D upgrade decreased the risk of HFH and improved reverse remodeling when compared to ICD, similar to that seen in patients in SR.