The aim of this study was to compare the decongestant properties and tolerability of the sympathomimetic xylometazoline hydrochloride 0.1% (CAS 1218-35-5, XMZ) and an oral formulation of cetirizine hydrochloride 5 mg and pseudoephedrine hydrochloride 120 mg (CAS 83881-51-0 and 90-82-4, CTZ/PSE; Cirrus). Thirty-six asymptomatic patients suffering from perennial allergic rhinitis from house dust mite were randomized to this open two-period crossover study. Patients received the study medications for four days each. In each period, treatments were taken twice a day. On day 1 in each period, immediately after the first dose of medication, patients were challenged with Dermatophagoides pteronyssinus extract 1 in the Vienna Challenge Chamber for 5 h. Primary efficacy parameters were nasal congestion evaluated by digital analysis of nasal cavity photographs and nasal airflow. Furthermore amounts of nasal secretions, nasal and ocular symptoms were recorded. In addition, 5 independent Ear-Nose-Throat specialists also assessed nasal cavity photographs. Statistical analyses were conducted at the 5% level of significance. Digital analysis of the nasal cavity photographs as well as nasal airflow measurements did not differentiate XMZ from CTZ/PSE. Ratings of the photographs of the nasal cavity emphasized the rapid onset of XMZ. No clinically relevant adverse events were recorded. This rapid onset of action but short-lived effect of topical xylometazoline 0.1% should be balanced against the consistent and prolonged effect of systemic cetirizine/pseudoephedrine combination in the treatment of perennial allergic rhinitis as no significant differences between these 2 medications were noted regarding their decongestant properties. With the exception of nasal obstruction, all subjective symptoms as well as the global condition were significantly better under CTZ/PSE. Amounts of nasal secretions during these sessions were significantly lower with CTZ/PSE.