Background <p><i>Cissus polyantha</i> (<i>C. polyantha</i>) Glig and Bradt is a climbing plant of the Vitaceae family generally distributed in tropical regions and used in traditional African pharmacopoeia for the treatment of conjunctivitis, pain, inflammation, microbial diseases and diabetes mellitus. The aim of this study was to evaluate the acute and subacute toxicity of the aqueous extract from leafy stems of <i>C. polyantha</i> (AECP) in rats.</p> Methods <p>In acute toxicity, AECP was administered orally at a single dose of 2000&#xa0;mg/kg. Clinical signs, general behavior and mortality were assessed for 14 days. In subacute toxicity, AECP at 111, 222 and 444&#xa0;mg/kg was administered orally for 28 days. Body weight, internal organ weight, water intake, food consumption, biochemical parameters, hematological profile and histological examinations were evaluated.</p> Results <p>Acute toxicity results showed no signs of poisoning and no mortality. The mean lethal dose (LD₅₀) of AECP was therefore greater than 2000&#xa0;mg/kg. In subacute toxicity, a significant increase in body weight, water and food consumption, liver weight and lymphocyte counts as well as a decrease in ALT activity and creatinine levels were recorded in rats of both sexes treated at 222 and/or 444&#xa0;mg/kg. AECP caused a notable reduction in uric acid, total cholesterol and triglycerides at all doses tested. Histopathological analysis of rat kidneys shows slight mesengial hyperplasia at 444&#xa0;mg/kg. However, all other parameters evaluated did not experience significant variation after AECP administration at all doses.</p> Conclusions <p>In acute toxicity, the LD₅₀ is greater than 2000&#xa0;mg/kg, so AECP is of low toxicity. In subacute toxicity, only the dose of 444&#xa0;mg/kg of AECP resulted in decreased body weight, water and food consumption, and increased liver weight, ALT activity, and lymphocyte counts. Doses below 444&#xa0;mg/kg may therefore be safe.</p>