Multisystem Langerhans cell histiocytosis (MS-LCH) is associated with high mortality when patients have risk organ involvement (RO(+)) or are younger than 2 years. In an international randomized trial, LCH-II, we intensified their treatment: arm A consisted of 6 weeks of daily prednisone and weekly vinblastine followed by 18 weeks of daily 6-mercaptopurine with vinblastine/prednisone pulses; etoposide was added in arm B. Considering all 193 randomized risk patients, there were similar outcomes: rapid (6 weeks) response (arm A vs arm B: 63%/71%), 5-year survival probability (74%/79%), disease reactivation frequency (46%/46%), and permanent consequences (43%/37%). However, (1) patients younger than 2 years without RO involvement (RO(-)) had 100% survival and uniformly high (> 80%) rapid response, (2) RO(+) patients not responding within 6 weeks had highest mortality, and (3) importantly, the more intensive arm B reduced mortality in RO(+) patients (relative hazard rate, accounting for differences in risk organ involvement, of 0.54; 95% CI = 0.29-1.00). Finally, comparison of RO(+) patients in LCH-I and LCH-II confirmed that increasing treatment intensity increased rapid responses (from 43% in arm A LCH-I to 68% in arm B LCH-II; P = .027) and reduced mortality (from 44% in arm A LCH-I to 27% in arm B LCH-II; P = .042). We conclude that intensified treatment significantly increases rapid response and reduces mortality in risk MS-LCH. This trial was registered at http://www.controlled-trials.com as no. ISRCTN57679341.