In vitro anti-HIV activity of various extracts prepared from the stem bark of Combretum molle (R. Br. Ex. G. Don.) Engl & Diels (Combretaceae), a plant widely used in Ethiopian traditional medicine for the treatment of liver diseases, malaria and tuberculosis has been assessed against human imnmuunodeficiencvy virus type 1 (HIV-1) and type 2 (HIV-2). The total extract was prepared by percolation with 80% methanol whilst the petroleum ether, chloroform, acetone and 100% methanol fractions were obtained by successive hot extraction using Soxhlet apparatus. Selective inhibition of viral growth was assessed by the simultaneous determination of the in vitro cytotoxicity of each of the extracts against MT-4 cells. Results obtained in this study indicate that the acetone fraction possessed the highest selective inhibition of HIV-1 replicatuon. Phytochemical investigation of the acetone fraction resulted in the isolation of two tannins and two oleanane-type pentacyclic triterpene glycosides. One of the tannins was identified as puncalagin (an ellagitannin), whilst the structure of the other (CM-A) has not yet been fully elucidated. The saponins that were characterized as arjunglucoside (also called 4-epi-sericoside) and sericoside did not inhibit replication of either HIV-1 or HIV-2. On the other hand, both punicalgin and CM-A displayed selective inhibition of HIV-1 replication with selectrvitv indices (ratio of 50% cytotoxic concentration to 50% effective antiviral concentration) of 16 and 25, respectivelvy and afforded cell protection of viral induced cytopathic effect of 100% when compared with control samples. Neither of the tannins exhibited a selective inhibition to HIV-2 replication at nontoxic doses.