OBJECTIVES: The current diagnostic management of patients with palpitations sometimes fails to establish a diagnosis. The aim of the Recurrent Unexplained Palpitations (RUP) study was to compare the diagnostic yield and the costs of prolonged monitoring strategy using an implantable loop recorder (ILR) with that of conventional diagnostic testing, in patients with infrequent unexplained palpitations. METHODS: RUP is a multicentrer, prospective, randomized study. We studied 50 consecutive patients (mean age 55±18 years, 33 females) without or with only mild heart disease, and with clinically significant, infrequent (>=1 episode per month), sustained (>1 minute) palpitations. Before enrolment, patients had a negative initial evaluation including ECG, 24 hour Holter monitoring, and blood chemistry examinations. Enrolled patients were randomized either to conventional strategy (n=24) or to ILR implantation (n=26). In order to evaluate the cost-effectiveness of ILR strategy, full hospital cost of procedures was calculated. RESULTS: In the conventional testing group a diagnosis was obtained in 5 patients (1 atrial fibrillation, 4 supraventricular tachycardia). In the ILR group a diagnosis was obtained in 19 subjects (2 sinus rhythm, 6 supraventricular tachycardia, 4 sinus tachycardia, 4 atrial fibrillation, 2 atrial flutter, 1 paroxysmal AV block). Thus, the diagnostic yield of ILR was significantly higher respect to conventional strategy (73% vs 21%, p<0.001). The average cost per patient was €1.410 in the conventional strategy group and €2.233 in the ILR group (p<0.001). Considering the total cost for each group, the cost per diagnosis was €6.767 and €3.056 respectively. CONCLUSION: The ICER obtained is low if compared to further examinations and acute events management necessary in case of less of diagnosis. The results of cost-effectiveness analysis could be useful to design further research protocols. Furthermore, these results could help decision makers to allocate resources based on cost-effectiveness evidences.