Homeostasis of metals plays an important role in functioning of the body. Not only the concentrations of toxic and essential metals in bodily fluids, but also their ability of interaction with proteins and enzymes defining the enzyme activity, are important. The study was aimed to compare the possibilities of binding interactions between various metal ions and human serum proteins. Chemical reactions between the immobilized metal ions (Cu²⁺, Zn²⁺, Mn²⁺, Ca²⁺, Fe³⁺, Mg²⁺, Hg⁺, Cd²⁺, Pb²⁺, Cr³⁺, Co²⁺, Ag⁺, Bi²⁺, Ba²⁺, Sr²⁺) and the serum proteins or highly purified blood metalloprotein (alpha-2-macroglobulin, α2M) were assessed by the crossed immunoelectrophoresis with in situ adsorption in the second dimension. It has been shown that Hg⁺, Cu²⁺, Zn²⁺, Cd²⁺ ions more actively interact with metalloproteins (particularly, with α2M) and many other human blood proteins in in vitro reactions than other ions. We have demonstrated that α2M interacts not only with Zn²⁺ and Cd²⁺ ions, as earlier reported, but also with Ca²⁺, Mg²⁺, Fe³⁺, Mn²⁺, Pb²⁺, Sr², Ag⁺. Interaction of a number of metal ions, including highly toxic ones, with blood proteins that are not metalloproteins has been revealed. The findings confirm the fundamental possibility of the metal ion imbalance active involvement in metabolic disorders via effects on the body's regulatory and transport proteins, which requires further investigation