Nasal polyposis (NP) has a great impact on quality of life (QOL) and its management involves a combination of medical therapy and surgery. To the authors' knowledge, no publication has extensively examined NP after optimal medical treatment based on subjective evaluations. The aim of this prospective study was designed to evaluate the QOL in NP patients after (1) a short course of oral steroids, (2) initial 3-month course of macrolide, and (3) long-term treatment with intranasal steroids. A total of 55 patients with grades I and II NP were consecutively treated with oral prednisolone at 25 mg in a single dose for 2 weeks, macrolide at 250 mg daily for the first 3 months, and long-term intranasal steroids. Patients were followed up and evaluated at baseline and 3, 6, and 12 months for QOL measure. At baseline, patients with grade I and grade II NP showed significantly worse QOL scores on all Rhinosinusitis Disability Index domains, particularly for physical function (4.59 ± 1.41) and were significantly higher in social function (3.16 ± 1.17). At 3, 6, and 12 months of treatment, patients showed a significant improvement in all impaired QOL domains compared with baseline after optimal medical therapy (p < 0.05). These results suggest that the optimal medical treatment to improve QOL incorporates medical polypectomy with a short course of oral steroids in addition to macrolide and this can be maintained by long-term intranasal steroid therapy.