Objective: To estimate national direct hospital costs associated with treatment of self-harm and to analyse whether costs differ with respect to demographic and clinical characteristics. Methods: A cohort design was applied to register data on all people living in Denmark (5.8 million inhabitants) from Jan 1, 2012 to Dec 31, 2016. Self-harm presentations at all hospitals by persons aged 10 years and older were included. Total costs and costs related to somatic and psychiatric care and treatment setting (inpatient, emergency department and outpatient) were calculated (in US dollars). The association between specific characteristics and somatic inpatient costs was analysed adjusted using generalized linear models and expressed as Odds Ratios (OR). Results: In all, 42,634 (97.3%) self-harm presentations by 30,366 persons were included. Annual somatic and psychiatric costs amounted to $25,241,518 and $34,696,388, respectively, and the median cost per episode was $2248 (IQR: $1553–$4138). Predictors of high somatic inpatient costs were: admission to intensive care (OR = 15.6; 95% CI, 13.7–17.9), particularly dangerous methods of self-harm, such as being hit by moving objects (OR = 6.5; 95% CI, 2.7–15.7) and shooting (OR = 6.0; 95% CI, 3.4–10.7), and age ≥75 years (OR = 1.8; 95% CI, 1.5–2.2). A small group of persons (0.7%) with ≥10 presentations accounted for 8.2% of somatic and 15.3% of total hospital costs. Conclusion: Substantial hospital costs were noted for inpatient treatment. Although one-time presenters accounted for the major share of costs, smaller patient groups accounted for considerable shares. Hospital costs of self-harm should be included in evaluation of initiatives for prevention and treatment.