Acquired cold urticaria is an infrequent physical urticaria that can provoke severe systemic reactions. Histamine is the primary mediator, but leukotrienes are also involved in the pathogenesis. H₁ antihistamines are recommended as first-choice treatment, but their efficacy is sometimes unsatisfactory. On the basis of pathogenic knowledge, it can be hypothesized that a combination therapy with antihistamines and leukotriene receptor antagonists is more effective than each drug given alone. We tested this hypothesis in 2 patients with severe systemic cold urticaria poorly responsive to conventional therapy. The patients underwent 3 consecutive treatment regimens (each of 2 weeks): cetirizine (10 mg once a day); zafirlukast (20 mg twice a day); and their combination. They were clinically evaluated, after each regimen, by means of a visual analog scale and ice-cube test. The combination therapy was superior to the 2 drugs given alone, as testified by subjective and objective evaluations.