Background: Earlier DC vaccine therapy demonstrated clinical benefit in some patients (pts) with advanced melanoma although the effect was seen only in pts with minimal tumor burden (ASCO2007 abstract No: 3077). As there is no effective treatment for high risk resected melanoma we conducted an exploratory trial to assess the effectiveness of DC vaccine in stage III and IV melanoma pts after radical surgery in comparison with observation. Methods: 108 stage III and IV melanoma pts were enrolled in two comparative arms. The arms were well balanced in respect with demographic and prognostic factors. The vaccine was based on mature autologous monocyte-derived DC primed with autologous tumor lysate, administered intradermally every 2-6 weeks until the disease progression. Disease free survival (DFS) and overall survival (OS) were evaluated with Kaplan-Meier method and compared between the two arms using the log rank test. Safety of DC vaccine was also monitored. Results: The vaccine arm included 56 pts (stage III – 46, stage IV – 10 pts) who were surgically rendered free of disease and treated with DC vaccine. 52 pts were enrolled in the control arm (stage III – 47, stage IV – 5 pts), they were treated surgically and observed afterwards. At a median follow-up of 22 months, the HR (DC vs observation) for DFS was 0.45 (p < 0.05; 95%CI 0.29-0.69) and for OS was 0.71 (p=0.23; 95%CI 0.40-1.25). 60% of pts in the DC arm remained alive at this time point. Risk reduction significantly correlated with the strong delayed type hypersensitivity reaction induced by vaccine in 31 (55%) out of 56 vaccinated pts. The vaccine was safe and well tolerated although vitiligo was registered in 4 cases which was associated with more durable time to progression and OS. Conclusions: The immunotherapy with DC vaccine is safe and significantly improves DFS compared with observation in the adjuvant treatment of stage III and IV melanoma.