Abstract Background The mortality risk remains significant in paediatric and adult patients on chronic haemodialysis (HD) treatment. We aimed to identify factors associated with mortality in patients who started HD as children and continued HD as adults. Methods The data originated from a cohort of patients <30 years of age who started HD in childhood (≤19 years) on thrice-weekly HD in outpatient DaVita dialysis centres between 2004 and 2016. Patients with at least 5 years of follow-up since the initiation of HD or death within 5 years were included; 105 variables relating to demographics, HD treatment and laboratory measurements were evaluated as predictors of 5-year mortality utilizing a machine learning approach (random forest). Results A total of 363 patients were included in the analysis, with 84 patients having started HD at <12 years of age. Low albumin and elevated lactate dehydrogenase (LDH) were the two most important predictors of 5-year mortality. Other predictors included elevated red blood cell distribution width or blood pressure and decreased red blood cell count, haemoglobin, albumin:globulin ratio, ultrafiltration rate, z-score weight for age or single-pool Kt/V (below target). Mortality was predicted with an accuracy of 81%. Conclusions Mortality in paediatric and young adult patients on chronic HD is associated with multifactorial markers of nutrition, inflammation, anaemia and dialysis dose. This highlights the importance of multimodal intervention strategies besides adequate HD treatment as determined by Kt/V alone. The association with elevated LDH was not previously reported and may indicate the relevance of blood–membrane interactions, organ malperfusion or haematologic and metabolic changes during maintenance HD in this population.