Adrenomedullin (AM) is a multifunctional peptide involved in roles as varied as blood pressure regulation, growth, neurotransmission, and inflammation control, among others. We previously identified complement factor H as a serum binding protein for AM and showed that factor H regulates AM functions and vice versa. Here we searched for the specific binding sites for AM by using recombinant fragments of factor H and a non-radioactive binding assay with fluorescein-tagged AM. By this methodology, two specific binding sites for AM were found in factor H. One of them shows a high affinity for AM and is located at the carboxy terminal end of factor H, comprising short consensus repeats (SCR) 15-20. Smaller fragments of this region did not bind to AM efficiently, suggesting that the high affinity binding site of factor H requires a complex three-dimensional structure to recognize AM. Another binding site with lower affinity for AM was found in the middle of the factor H molecule, at SCR 8-11. Antibodies against factor H prevented AM binding altogether, but the main binding partner of factor H, C3b, did not, indicating that C3b and AM bind to different regions of factor H. These structure-function data support previous biochemical observations. Our understanding of the binding between AM and factor H may help in the development of new treatments for diseases in which these molecules play active roles.