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Background Colchicine seems to be a good drug for treating recurrences of pericarditis after conventional treatment failure, but no clinical trial has tested the effects of colchicine as first-line drug for the treatment of the first recurrence of pericarditis. Methods A prospective, randomized, open-label design was used to investigate the safety and efficacy of colchicine therapy as adjunct to conventional therapy for the first episode of recurrent pericarditis. Eighty-four consecutive patients with a first episode of recurrent pericarditis were randomly assigned to receive conventional treatment with aspirin alone or conventional treatment plus colchicine (1.0-2.0 mg the first day and then 0.5-1.0 mg/d for 6 months). When aspirin was contraindicated, prednisone (1.0-1.5 mg/kg daily) was given for 1 month and then was gradually tapered. The primary end point was the recurrence rate. Intention-to-treat analyses were performed by treatment group. Results During 1682 patient-months (mean follow-up, 20 months), treatment with colchicine significantly decreased the recurrence rate (actuarial rates at 18 months were 24.0% vs 50.6%; P = .02; number needed to treat = 4.0; 95% confidence interval 2.5-7.1) and symptom persistence at 72 hours (10% vs 31%; P = .03). In multivariate analysis, previous corticosteroid use was an independent risk factor for further recurrences (odds ratio, 2.89; 95% confidence interval, 1.10-8.26; P = .04). No serious adverse effects were observed. Conclusion Colchicine therapy led to a clinically important and statistically significant benefit over conventional treatment, decreasing the recurrence rate in patients with a first episode of recurrent pericarditis.