This study evaluated the effect of mometasone furoate nasal spray (MFNS) on health-related quality of life (HRQoL) in patients with acute, uncomplicated rhinosinusitis. In a randomized, double-blind, placebo-controlled trial, HRQoL was assessed in 340 patients using the SinoNasal Outcome Test (SNOT)-20 questionnaire at baseline and after 15 days of treatment with MFNS 200 g once-daily (q.d.) or twice-daily (b.i.d.), amoxicillin 500 mg three times daily (t.i.d.), or placebo. Baseline mean total scores for SNOT-20 were similar in the four groups (2.15-2.23). At endpoint, there was a statistically significant improvement in mean total score only with MFNS 200 g b.i.d. (p = 0.047 versus placebo). MFNS was associated with numerical improvements in all SNOT-20 items compared with placebo. Treatment with MFNS 200 g b.i.d. is associated with a significant improvement in HRQoL compared with placebo in patients with acute, uncomplicated rhinosinusitis.