Increasing evidence suggests that free haem and iron exert vasculo‐toxic and pro‐inflammatory effects by activating endothelial and immune cells. In the present retrospective study, we compared serum samples from transfusion‐dependent patients with β‐thalassaemia major and intermedia, hereditary spherocytosis and sickle cell disease (SCD). Haemolysis, transfusions and ineffective erythropoiesis contribute to haem and iron overload in haemolytic patients. In all cohorts we observed increased systemic haem and iron levels associated with scavenger depletion and toxic ‘free’ species formation. Endothelial dysfunction, oxidative stress and inflammation markers were significantly increased compared to healthy donors. In multivariable logistic regression analysis, oxidative stress markers remained significantly associated with both haem‐ and iron‐related parameters, while soluble vascular cell adhesion molecule 1 (sVCAM‐1), soluble endothelial selectin (sE‐selectin) and tumour necrosis factor α (TNFα) showed the strongest association with haem‐related parameters and soluble intercellular adhesion molecule 1 (sICAM‐1), sVCAM‐1, interleukin 6 (IL‐6) and vascular endothelial growth factor (VEGF) with iron‐related parameters. While hereditary spherocytosis was associated with the highest IL‐6 and TNFα levels, β‐thalassaemia major showed limited inflammation compared to SCD. The sVCAM1 increase was significantly lower in patients with SCD receiving exchange compared to simple transfusions. The present results support the involvement of free haem/iron species in the pathogenesis of vascular dysfunction and sterile inflammation in haemolytic diseases, irrespective of the underlying haemolytic mechanism, and highlight the potential therapeutic benefit of iron/haem scavenging therapies in these conditions.