Introduction: The primary objective of treatment of inflammatory diseases of the upper respiratory tract (rhinitis, uncomplicated sinusitis) with local decongestants is to relieve obstruction and to improve associated symptoms. Restoration of unrestricted respiration and drainage of the nasal sinuses reduce the risk of further complications (i.e. chronicity). Objective: To determine whether the therapeutic effects of the homeopathic complex remedy Euphorbium compositum nasal drops SN are comparable to those of xylometazoline with respect to efficacy and tolerability. Methods: Open, multicenter, prospective, active-controlled cohort study in patients with inflammatory processes and diseases of the upper respiratory tract. The primary outcome was to demonstrate non-inferiority of the homeopathic complex remedy to xylometazoline. Results: Clinically relevant reductions in the intensities of disease-specific symptoms were observed with both therapies. Non-inferiority of the homeopathic complex remedy to xylometazoline could be shown for all studied variables and in no case did the lower boundary of the 95% confidence interval cross the threshold of 0.5 score points. Tolerability was good with for both therapies. Conclusions: This cohort study indicates a comparable efficacy and tolerability profile of the homeopathic complex remedy Euphorbium compositum nasal drops SN and the reference substance xylometazoline in patients with inflammatory processes and diseases of the upper respiratory tract.