The Folin-Denis assay using the Folin-Ciocalteu (F-C) reagent has been commonly used for analyzing the total phenolic compound content in various food products. In the present study, the effects of proteins on the reactivity of the F-C reagent with different phenolic compounds were investigated. Bovine serum albumin (BSA) or skim milk proteins showed a concentration-dependent increase in color response in the Folin-Denis assay; these proteins decreased the color response of most phenolic compounds tested. The reactivity of phenolic compounds was significantly less pronounced in the presence of BSA and this interference was greater at higher concentrations of phenolic compounds. The reactivity of phenolic compounds with the F-C reagent was reduced significantly by their oxidation; the reaction of the oxidized products with the F-C reagent was more severely affected by BSA. The interfering effects in the Folin-Denis assay might be attributable to binding interactions of phenolic compounds with proteins.