The objective of the study was to reveal if mometasone furoate nasal spray as monotherapy or combined with long-term oral clarithromycin have influence on biofilms in chronic rhinosinusitis with polyps. The study is a randomized controlled trial in a tertiary referral hospital. Thirty-four patients with chronic rhinosinusitis completed the study. In the first group, 19 patients received mometasone furoate nasal spray 200 mu g once daily for 8 weeks. In the second group, 15 patients received oral clarithromycin 500 mg twice daily for 2 weeks and continued once daily 250 mg tablet for subsequent 6 weeks, plus mometasone furoate. Scanning electron microscopy was the primary outcome measure. Secondary outcome measures included computerized tomography and sinonasal outcome test-20 items. Mucosal biofilms were detected in 23 of 34 (68 %) patients on pretreatment polyp samples. After the treatment, biofilms disappeared in 1 of 11 patients in the first group, whereas the eradication of biofilms was evident in 6 of 12 (50 %) patients in the second group. Tomography scores improved in eight patients of each group (42.1 and 53.4 %, respectively). The comparison of improvements did not reveal significant difference between the groups. The overall symptom scores improved compared to the baseline levels. The mean changes of -8.8421 and -11.4000 in the first and second group, respectively, were not statistically different. Adding long-term low-dose oral macrolides to nasal steroids was effective in the eradication of biofilm. However, we were not able to demonstrate that combined therapy was superior in terms of the improvement in tomography and symptom scores.