© 2016, The Japanese Society of Hematology. The JLSG-96 study reported very low mortality rates for children newly diagnosed with multifocal Langerhans cell histiocytosis (LCH). The JLSG-02 study was performed to further improve the prognosis from 2002 to 2009. The present study compared the therapeutic results of these two studies in terms of multisystem disease. All patients were treated with 6 weeks of the Induction A regimen, comprising cytarabine, vincristine and prednisolone, followed by maintenance therapy. Poor responders to Induction A were switched to Induction B. JLSG-02 has been revised from JLSG-96 in the following respects: prednisolone dosage during Induction A increased; duration of maintenance therapy extended from 24 to 48 weeks; cyclosporine introduced to Induction B for progressive disease. One hundred forty-seven children with multisystem LCH were evaluated. Of these, 84 were positive for risk of organ involvement (RO) and 63 were RO-negative. At the 6-week point, 76.2 % of RO+ and 93.7 % of RO− patients responded to Induction A. Five-year event-free survival (EFS) was 46.2 % [95 % confidence (CI), 35.5–56.9] for RO+ and 69.7 % (58.4–81.1) for RO−, which was significantly superior to that in JLSG-96 [26.8 % (13.3–40.4) and 38.9 % (16.4–61.4), respectively]. The intensified induction and prolonged maintenance regimens in JLSG-02 improved EFS in patients with multisystem LCH.