Objectives: Evaluate factors related to improvement after doxycycline treatment for patients with recurrent chronic rhinosinusitis with nasal polyps. Methods: We conducted an open label study from 2012 to 2013 on 32 patients with difficult-to-treat chronic rhinosinusitis with nasal polyps uncontrolled after endoscopic sinus surgery and long-term low-dose clarithromycin treatment. Patients received doxycycline 100mg per day for 12 weeks after a three-month wash-out period. The main outcome measure was a meaningful improvement in SNOT-20 (>0.80). Other outcome measures were the SNOT-20, NOSE, and Lund-Kennedy scores. The following parameters were analyzed: asthma, rhinitis, DREA, and blood testing before treatment for C3, C4, IgG, IgA, IgE, IgM, ANCA, and blood eosinophil count. Results: 53.1% (17/32) of patients showed a clinically significant improvement in SNOT-20 (>0.8) score after treatment. The patients also showed a statistically significant improvement in SNOT-20 (p<0.001), Lund-Kennedy (p<0.001), and NOSE (p<0.004) scores. Presence of asthma (p<0.001), AERD (p<0.008), increased level of blood eosinophil count, and increased serum IgE (p<0.018) were factors associated with a worse prognosis after treatment. Conclusions: Our group of patients showed a positive result after treatment with doxycycline, especially in patients without asthma, DREA, andincreased serum levels of IgE and eosinophil counts.