Aims: Non-device related right-sided infective endocarditis (ND-RSIE) is not well characterized. We aimed to characterize patients with infective endocarditis (IE) with emphasis on the epidemiology, clinical characteristics and complications of ND-RSIE. Methods: In this population-based cohort study, we identified patients with IE using ICD-10 codes from the Danish National Hospital Register in the Region of Southern Denmark between January 2007 and May 2017. Hospital records were reviewed, and characteristics and outcomes recorded. Results: We included 1243 confirmed IE episodes of which 82% were left-sided IE, 11% were cardiac device right sided infective endocarditis (RSIE) and 7% were ND-RSIE. Patients with ND-RSIE were considerably younger, had less comorbidity and had a lower 30-day mortality (6%) compared with patients with device RSIE (24%) and left-sided IE (26%) (p < 0.01). ND-RSIE was associated with underlying heart disease, involvement of the tricuspid valve (57%), Staphylococcus species (53%) and complications (61%). Forty percent of ND-RSIE occurred among people who inject drugs (PWID) for whom significant differences were observed compared with non-PWID with regards to tricuspid valve involvement (96% vs. 32%), causative microorganisms (Staphylococcus aureus 79% vs. 27%), complications (86% vs. 45%), recurrence (29% vs. 11%) and 30-day mortality (0% vs. 7%). Conclusion: ND-RSIE is relatively rare and differs with regards to epidemiology, clinical characteristics and complications compared with left-sided IE and cardiac device RSIE, but has a favourable prognosis. Forty percent of ND-RSIE occurs among PWID, which is associated with frequent complications but a very low mortality.