Patients with severe chronic urticaria may not respond to antihistamines, and other systemic treatment options may either be ineffective or associated with unacceptable side effects. We present data on efficacy and safety of adalimumab and etanercept in 20 adult patients with chronic urticaria. Twelve (60%) patients obtained complete or almost complete resolution of urticaria after onset of therapy with either adalimumab or etanercept. Further three patients (15%) experienced partial response. Duration of treatment ranged between 2 and 39 months. Those responding completely or almost completely had a durable response with a mean of 11 months. Six patients (30%) experienced side effects and five patients had mild recurrent upper respiratory infections, whereas one patient experienced severe CNS toxicity that could be related to treatment with TNF-alpha inhibitor. Adalimumab and etanercept may be effective and relatively safe treatment options in a significant proportion of patients with chronic urticaria who do not respond sufficiently to high-dose antihistamines or in whom standard immunosuppressive drugs are ineffective or associated with unacceptable side effects.