Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small- and medium-sized arteries with multiorgan involvement, rarely reported in childhood. Despite aggressive treatment with the combination of corticosteroids and cytotoxic agents, the overall prognosis is poor in most patients. We report on two siblings, now 15- and 14-year-old, affected with childhood onset PAN, refractory to multiple therapies, who showed rapid clinical and laboratory improvement when mycophenolate mofetil was introduced. The relationship between the administration of this immunosuppressant agent and the reduced disease activity is confirmed by the sustained absence of disease flares over 4 years of treatment.