Introduction: Most relapses in HL patients (pts) occur within 5 yrs from diagnosis. However, there are pts who do relapse later on, even after decades. The exact incidence of VLRs, especially after CT/CMT, is not well established. Similarly, there are very limited data on baseline disease features associated with VLRs as well as the outcome of these pts. Aim: The estimation of the probability of VLR in pts with HL who remain in 1st complete remission (CR1) for 5 years after institution of CT/CMT, the identification of risk factors for VLR and the evaluation of the outcome of VLRs. Pts/Methods: Retrospective study of 764 HL pts in CR1 for ≥5 years. Initial CT was anthracycline-based in 87% of pts [mainly A(E)BVD] and MOPP-like in 13%. The Kaplan-Meier method and Cox’s model were used for univariate and multivariate survival analysis. Results: Among 764 pts, 44 had a VLR (2/44 had a composite HL and non-Hodgkin lymphoma): 24, 13, 4 and 3 between 5-10, 10-15, 15-20 and beyond 20 years from diagnosis. Starting from diagnosis, the 10-year and 15-year VLR rate were 3.7% and 8.0%. In univariate analysis, higher risk for VLR was observed for pts treated with CT only vs. CMT (p=0.0006), non-nodular sclerosing histologies (non-NS) (p=0.002) and age ≥45 yrs (p=0.02). In multivariate analysis, independent predictors of VLR were non-NS (HR 2.39, p=0.006) and CT vs. CMT (HR 2.56, p=0.003). At 15 yrs from diagnosis, the probability of VLR was 3.0%, 10.3% and 24.0% (p<0.0001) for pts with 0, 1 and 2 risk factors (RFs). Among 663 anthracycline-treated pts, independent predictors for VLR were non-NS histologies (HR 2.56, p=0.02) and age ≥45 yrs (HR 2.29, p=0.04). At 15 yrs from diagnosis, the probability of VLR was 2.7%, 10.8% and 27.3% (p<0.0001) for patients with 0, 1 and 2 RFs. Conventional salvage therapy was given to 37 pts (mostly non-cross resistant), 4 received salvage RT only, 2 salvage with autoSCT, while 1 pt has not received salvage therapy yet. The 5- and 10-yr survival after failure was 70% and 42%. Conclusions: Among pts with HL who remain in CR1 at 5 years following CT w/wo RT, approximately 3-4% relapse within the next 5 yrs and even more thereafter. This observation if important when counselling pts in CR1 regarding their chance of ultimate cure. Younger pts with NS who receive CMT have the lowest risk for VLR. AutoSCT should not be spared solely on the basis of a very long CR1, since the results of conventional salvage do not appear satisfactory.