Introduction: The relapse of nasal polyps after surgical treatment still remains an unsolved medical problem and, at the same time, a challenge for researchers. Objective: Considering that edema, vessel dilatation and inflammatory cells infiltration are the histopathological characteristics of nasal polyps, our aim was to demonstrate the long-term efficacy of intranasal furosemide, an inhibitor of the sodium-chloride co-transporter channel at the basolateral surface of the respiratory epithelial cell versus intranasal mometasone furoate (a topical nasal steroid) or no therapeutic intervention in preventing relapses of chronic hyperplastic sinusitis with nasal polyposis (CHS-NP). Methods: 170 patients with bilateral obstructive or sub-obstructive rhinosinusal polyposis were surgically treated in the Department of Otorhinolaryngology at the University of Siena. One month after surgery group I patients (97) started treatment with intranasal furosemide, group II patients (40) received no therapeutic treatment and group III patients (33) were treated with an intranasal steroid (mometasone furoate). Results: Patients treated with furosemide did not have relapses in 82.5% of cases; in contrast to those of group I, group II and group III patients had successful treatment in 75.8% and 70%, respectively. Moreover, we noted a prevalence of early stage relapse in patients treated with furosemide or mometasone furoate, whereas patients who did not receive any treatment experienced more severe grades of relapses (p < 0.005). Conclusion: Intranasal furosemide nasal spray represents a valid therapeutic treatment in the prevention of relapsing rhinosinusal polyposis.