[show abstract][hide abstract] ABSTRACT: Background: Avian influenza A (H5N1) virus is one of the most important public health concerns worldwide. The antiviral activity of native and esterified whey proteins fractions (a-lactalbumin, b-lactoglobulin, and lactoferrin) was evaluated against A/chicken/Egypt/086Q-NLQP/2008 HPAI (H5N1) strain of clade 2.2.1 (for multiplicity of infection (1 MOI) after 72 h of incubation at 37°C in the presence of 5% CO 2) using MDCK cell lines. Result: Both the native and esterified lactoferrin seem to be the most active antiviral protein among the tested samples, followed by b-lactoglobulin. a-Lactalbumin had less antiviral activity even after esterification. Conclusion: Esterification of whey proteins fractions especially lactoferrin and b-lactoglobulin enhanced their antiviral activity against H5N1 in a concentration dependent manner.