Diabetes is characterized by an elevated level of glucose in the blood. This glucose can form covalent adducts with plasma proteins through a non-enzymatic process known as glycation. It has been suggested that the increasing glycation can influence the ability of plasma proteins to bind to small molecules. Herein, the difference between healthy human plasma proteins (HPP) and type II diabetes plasma proteins (TPP) in binding small molecules was investigated. TPP showed about 1–10 times lower affinities for polyphenols than HPP. The values of lg K_a(HPP) are positive proportional to the values of lg K_a(TPP) with excellent linear relationship. The glycation of HPP decreased the affinities for HPP by about 1.17 to 16.6 times. The difference between HPP–polyphenol interaction and TPP–polyphenol interaction was bigger for the more lipophilic polyphenols. The affinities for TPP or HPP slightly decreased with increasing hydrogen bond donor numbers of polyphenols and hardly changed with hydrogen bond acceptor numbers.