Background: The human immunodeficiency virus (HIV)/acquired immunodeficiencysyndrome (AIDS) has always been a global health threat and leading cause of deaths. However,due to the emergence of drug-resistant HIV, an inevitable consequence of increasing use of antiret-roviral drugs posed a major threat to antiretroviral therapy success.Objective: The discovery of anti-HIV-1 agents will be used for the effective treatment ofHIV/AIDS.Method: In continuation of our program aimed to discover anti-HIV-1 agents, twelve matrine de-rivatives, such as 14-formyl-15-aryloxy/methoxymatrines (3a-j) and 14-aryloxymethylidenyl-matrines (3k,l), were semi-prepared from matrine, and evaluated against HIV-1 ? B replication inacutely infected C8166 cells in vitro.Results: Among them, compound 3j showed the most potent anti-HIV-1 activity with EC 50 andtherapeutic index (TI) values of 1.79 ?g/mL, and 98.2, respectively.Conclusion: It has been demonstrated that the positions of methyl on the phenyl ring and 14-formylmatrine-15-oxy on the naphthyl ring were very important for the activity. It will lay thefoundation for further structural modification and application of matrines as HIV-1 inhibitors.