Phyllanthus amarus derived preparations were previously shown to inhibit RT inhibitor-resistant HIV variants as efficiently as wild-type strains. The drugs target different steps of the HIV life cycle, thereby presenting multiple antiviral activities. Here we show that a water/alcohol extract blocks HIV-1 attachment and the HIV-1 enzymes integrase, reverse transcriptase and protease to different degrees. A gallotannin containing fraction and the isolated ellagitannins geraniin and corilagin were shown to be the most potent mediators of these antiviral activities. The P. amarus derived preparations blocked the interaction of HIV-1 gp120 with its primary cellular receptor CD4 at 50% inhibitory concentrations of 2.65 (water/alcohol extract) to 0.48 microg/ml (geraniin). Inhibition was also evident for the HIV-1 enzymes integrase (0.48-0.16 microg/ml), reverse transcriptase (8.17-2.53 microg/ml) and protease (21.80-6.28 microg/ml). In order to prove the in vivo relevance of these biological activities, plant material was administered orally to volunteers and a potent anti-HIV activity in blood could be demonstrated. Sera at a final concentration of 5% reduced HIV replication by more than 30%. These results support the conclusion that P. amarus has inhibitory effects on HIV not only in vitro but also in vivo.