Objective. To investigate the tolerability and impact on quality of life of liposomal nasal spray compared to guideline-recommended steroid-based therapy in patients with chronic rhinosinusitis. Symptom reduction and use of antisymptomatic medication were also examined. Methods. In this monocenter, prospective, controlled, open, and noninterventional study, 60 patients with chronic rhinosinusitis were treated with liposomal nasal spray and 30 patients received steroid-based therapy. The study comprised five visits occurring at intervals of two to four weeks. Efficacy was determined according to the sinusitis symptom score documented daily. The polyp score was recorded at the initial and final visits. Tolerability was determined through the Nasal Spray Evaluation Questionnaire, and quality of life was ascertained with the SNOT-20 Score. Results. Both treatments achieved a significant reduction of sinusitis symptoms (P < 0.05) and also rhinoscopic improvement (P < 0.05). The majority of patients assessed the treatments as "good" or "very good," and the quality of life improved significantly (P < 0.05). There was no significant difference in symptom reduction, QoL, and endoscopic exams between both treatments. Conclusion. The treatment of chronic rhinosinusitis with liposomal nasal spray results in a similar, significant reduction of symptoms and significant improvement in quality of life as guideline-recommended treatment and is therefore a comparable alternative.