Despite advances in more recent years, the pathophysiology and especially treatment modalities of thrombotic microangiopathy (TMA) largely remain enigmatic. Disruption of endothelial homeostasis plays an essential role in TMA. Considering the proven causal association between magnesium and both endothelial function and platelet aggregability, we speculate that a magnesium deficit could influence the course of TMA and the related haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. A predisposition towards TMA is seen in many conditions with both extracellular and intracellular magnesium deficiency. We propose a rationale for magnesium supplementation in TMA, in analogy with its evidence-based therapeutic application in pre-eclampsia and suggest, based on theoretical grounds, that it might attenuate the development of TMA, minimise its severity and prevent its recurrence. This is based on several lines of evidence from both in vitro and in vivo data showing dose-dependent effects of magnesium supplementation on nitric oxide production, platelet aggregability and inflammation. Our hypothesis, which is further amenable to assessment in animal models before therapeutic applications in humans are implemented, could be explored both in vitro and in vivo to decipher the potential role of magnesium deficit in TMA and of the effects of its supplementation.