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Simple Summary: Recent ESC Atrial Fibrillation guidelines introduced some changes in the options for rate control, such as the possibility to combine beta-blockers and non-dihydropyridine calcium channel blockers to address the need for a personalised pharmacologic rate control treatment for AF. However, there are limited data on this topic. This real-world prospective observational study aims to explore the prognostic impact of a patient-specific therapy for rate control in atrial fibrillation, including the use of non-dihydropyridine calcium channel blockers in patients with heart failure or in combination with beta-blockers, compared to standard rate control therapy, as defined by previous ESC guidelines. We performed an analysis of 1112 patients on exclusive rate control treatment referred to our University Hospital. Our results showed no difference in the one-year overall survival in the patient-specific therapy group compared to the standard treatment group. The use of non-dihydropyridine calcium channel blockers for rate control in patients with atrial fibrillation, either alone or in combination with beta-blockers, showed clinical benefit in selected patients, including a group of subjects with heart failure. Future controlled studies are needed to confirm our findings and identify subjects who will obtain greater benefit from such patient-specific rate-control strategies. Atrial fibrillation (AF) is a multifaceted disease requiring personalised treatment. The aim of our study was to explore the prognostic impact of a patient-specific therapy (PT) for rate control, including the use of non-dihydropyridine calcium channel blockers (NDDC) in patients with heart failure (HF) or in combination with beta-blockers (BB), compared to standard rate control therapy (ST), as defined by previous ESC guidelines. This is a single-centre prospective observational registry on AF patients who were followed by our University Hospital. We included 1112 patients on an exclusive rate control treatment. The PT group consisted of 125 (11.2%) patients, 93/125 (74.4%) of whom were prescribed BB + NDCC (±digoxin), while 85/125 (68.0%) were HF patients who were prescribed NDCC, which was diltiazem in all cases. The patients treated with a PT showed no difference in one-year overall survival compared to those with an ST. Notably, the patients with HF in ST had a worse prognosis (p < 0.001). To better define this finding, we performed three sensitivity analyses by matching each patient in the PT subgroups with three subjects from the ST cohort, showing an improved one-year survival of the HF patients treated with PT (p = 0.039). Our results suggest a potential outcome benefit of NDCC for rate control in AF patients, either alone or in combination with BB and in selected patients with HF. [ABSTRACT FROM AUTHOR]