A series of chiral gossypol derivatives and its analogs were synthesized and tested in vitro for their anti-H 5 N 1 activity. Interestingly, (+)-gossypol derivatives and its analogs were more active against H 5 N 1 than the corresponding (−)-gossypol derivatives and its analogs. Through a simple chemical modification with amino acids, less active chiral gossypol could be converted into more active derivatives, and most of chiral gossypol derivatives were more potent against H 5 N 1 than 1-adamantylamine. With regard to the mechanism of action, chiral gossypol derivatives and its analogs might impair the virus entry step of cell infection, likely targeting to HA2 protein.