8506b Background: EORTC 18991 is the largest adjuvant trial ever conducted in stage III melanoma. It assessed the efficacy and toxicity of long-term PEG-IFN vs Observation (Obs.). METHODS PEG-IFN (Induction at 6µg/Kg/wk, sc, 8 weeks; followed by Maintenance at 3µg/Kg/wk, sc) for a total treatment duration of up to 5 years was compared to Obs. in 1256 patients (pts) with stage III melanoma (anyTN1-2M0 without in-transit metastases). Randomization was stratified for nodal involvement N1 (microscopic) vs N2 (palpable nodes), # of nodes, Breslow and ulceration of primary, sex and center. Distant metastasis-free survival (DMFS) was the primary endpoint. Relapse-free survival (RFS) was the pre-specified regulatory primary endpoint. Overall survival (OS) was the secondary endpoint. Intent-to-treat analysis was performed Results: Median follow-up was 7.6 yrs is shown in the table. CONCLUSIONS Long-term PEG-IFN therapy in stage III melanoma had a significant and sustained impact on RFS, but not on DMFS and OS. Pts with only microscopic nodal involvement (sentinel node positive) seemed to have a greater benefit of PEG-IFN in terms of RFS, and marginally regarding DMFS and OS. In the smaller subgroup of pts with sentinel node positive and with ulcerated melanoma, the benefit seemed to be the most striking and consistent regarding all endpoints, and was maintained at long term follow-up. These effects have been observed in 2 consecutive EORTC trials (18952 and 18991) involving 2,644 pts. [Table: see text].