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Tragia brevipes and Tetradenia riparia have been widely used in traditional medicine. T. brevipes relief stomach pain and in treatment of rheumatism while T. riparia; heal chest pains, stomach-ache, malaria and act as antioxidant. However, scanty data exist on their potential anticancer activity. The total phenolic content was determined and anti-proliferative activity of the Methanol-Dichloromethane extract from the leaves evaluated against cancerous cell lines. The total phenolic content of the plants extract was determined using an UV visual spectrophotometer at 765 nm. The 3- (4-5-dimethyl-2-thiazoly)-2, 5-diphenyltetrazolium bromide (MTT) cell proliferation bioassay was used to test for anti-proliferative activity on Hela (cervical), DU145 (prostrate) and HCC (breast) cancer cell lines and Vero (normal) cell. T. brevipes and T. riparia had a phenolic concentration of 30.44 and 20.25 µg/ml, respectively. Both plants showed anti-proliferative activity on cancer cells with the most inhibited being DU145 with an IC50 of 29.67 ± 4.60 µg/ml for T. brevipes and 11.45 ± 0.87 µg/ml for T. riparia. The standard 5 Fluorouracil had an IC50 of 5.04 ± 4.12 µg/ml on DU145. T. riparia had the highest antiproliferative activity of 65.54 ± 16.85 µg/ml on Hela cells and 62.84 ± 1.10 µg/ml on HCC. T. brevipes had an IC50 of 661.11 ± 15. 12 µg/ml on Hela cells and 703.09 ± 18.35 µg/ml on HCC. Extracts from both plants were highly selective on DU145 cancer cells with a selectivity index (SI) of 21.62 for T. brevipes and 7.88 for T. riparia. Methanol-Dichloromethane extracts from T. brevipes and T. riparia exert anti-proliferative activity, however, the active compound (s) and the mechanisms of anti-proliferative action need to be investigated further.