Objectives: Direct-acting antiviral agents (DAAs) have modified the management of chronic hepatitis C virus (HCV) infection, including HCV-related cryoglobulinemia vasculitis (CryoVas). However, patients might experience vasculitis relapse, and no reliable predictors of CryoVas relapse following sustained virological response (SVR) have been established. We aimed to describe HCV-CryoVas relapse rates and factors associated with it. Methods: International multicenter cohort where patients with HCV-CryoVas from Egypt, France and Italy treated with DAA were analyzed retrospectively. Factors associated with relapse-free survival were evaluated in a multivariate adjusted model. Results: Out of 913 patients, 911 (99.8%) obtained SVR. After 35 months of median follow-up, 798 patients (87.4%) had sustained remission of vasculitis, while 115 (12.6%) experienced CryoVas relapse. By the time of relapse, skin involvement was present in 100%, renal involvement in 85.2%, and peripheral neuropathy in 81.7%. Relapses were treated with glucocorticoids in 90.9%, associated with plasma exchange, cyclophosphamide or rituximab in 50%, 37.3% and 6.4%, respectively. The cumulative incidence of CryoVas relapse was 0.7% (95%CI 0.3;1.4), 12.3% (95%CI 10.2;14.6) and 13.1% (95%CI 11.0;15.5) at 12, 24 and 36 months after DAA treatment, respectively. Independent baseline risk factors associated with CryoVas relapse were male sex, skin ulcers and kidney involvement at baseline and peripheral neuropathy at the end of DAA treatment. Death occurred in 11 relapsers, mainly due to infections. Conclusions: A substantial proportion of CryoVas patients experience relapse after DAA-induced SVR. Relapses are moderate-to-severe, and impact survival after 24 months, mainly due to infections. Independent risk factors for relapse or death were found.