This study evaluates the effectiveness and safety of cyclosporine (CsA) in the treatment of patients with chronic idiopathic urticaria with a positive autologous serum skin test (ASST), who fail to respond to conventional therapy, and requiring long-term oral steroid treatment. In a double-blind study, 40 adults were assigned randomly to receive CsA (5 mg/kg per day for 8 weeks and then 4 mg/kg per day for 8 weeks) or cetirizine (10 mg/day) and then they were followed up for 9 months. After 2 weeks, the study was opened because 16 patients (40%) had daily severe relapses requiring systemic steroids treatment. All of these patients had been receiving antihistamines and, therefore, all patients also were assigned to the CsA treatment regimen (5 mg/kg per day for 8 weeks and then 4 mg/kg per day for 8 weeks). The ASST and clinical severity score were evaluated before and after treatment. All of the 40 patients completed the 16-week CsA course without dropping out because of relevant side effects. In three patients, CsA was reduced by 0.5 mg/kg per day after the 1st month of treatment for a mild and reversible increase in serum creatinine. During CsA treatment, 20 patients had relapses resolving spontaneously (8 patients) or with antihistamines (12 patients). During the 9-month follow-up period, 22 patients had relapses resolving spontaneously (10 patients) or with antihistamines (12 patients). Only two patients failed to complete the study because of severe symptoms occurring after 4 and 7 days of follow-up and requiring long-term steroid treatment. After 9 months of follow-up, 16 patients were still in full remission. The clinical severity score of chronic idiopathic urticaria dropped significantly by the end of the 4th month of treatment (p = 0.002) as well as by the completion of follow-up (p = 0.007). The ASST was negative in 13 patients and positive in 3 of 16 patients, with total remission of symptoms. Significant score reduction also was observed in patients experiencing relapses that resolved spontaneously (p = 0.005) or with antihistamines (p = 0.03). These results show the long-term efficacy and tolerability of CsA in patients with severe chronic idiopathic urticaria, unresponsive to conventional treatments.