The affinity of AtO+ for around 20 model ligands (L), carrying functionalized oxygen, sulfur, and nitrogen atoms, has been assessed through a combined experimental and theoretical methodology. Significant equilibrium constants (K-L similar to 10(4)) have been measured for sulfur-containing compounds, in agreement with the previously highlighted, relatively stable radiolabeling of SH-containing proteins with At-211. Conversely, no interaction occurs in the aqueous phase for their oxygenated counterparts, but higher affinities (K-L > 10(6)) have been determined for nitrogen-based ligands, including aromatic nitrogen heterocycles. The quantum mechanical calculations definitively ruled out any rationale based on either the metallic character of astatine or its guessed softness; the favored interactions all involve specifically the oxygen atom of AtO+, leading to the formation of covalent O-S or O-C single bonds.