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Background Intravenous drug abuse (IDA) is a known risk factor for infective endocarditis (IE) and is associated with frequent relapses, but its prognostic impact is still debated. The potential futility of surgery in this population is a further issue under discussion. We aimed to describe the clinical characteristics, the therapeutic strategy, and the prognosis associated with IDA in IE. Methods We retrospectively analysed 440 patients admitted to a single surgical centre for definite active IE from January 2012 to December 2020. Results Patients reporting IDA (N = 54; 12.2%) were significantly younger (p Conclusions IE secondary to IDA affects younger patients than those with IE not associated with IDA. Probably due to this difference, IE secondary to IDA is not associated with significantly higher mortality, whereas the negative, long-term prognostic impact of IDA emerges in multivariate analysis. Considering the good prognosis of patients with uncomplicated IE treated medically, surgery should be reserved to patients with a strict- guidelines-based indication. However, since there are no clear predictors of an unfavourable risk–benefit ratio of surgery in patients with surgical indication, all patients with a complicated IE should be operated, irrespective of a history of IDA.