Sutherlandia frutescens (SF), an indigenous medicinal plant to South Africa, is traditionally used to treat a diverse range of illnesses. More specifically, the immune-enhancing potential of SF has been recognised to the extent that SF extracts have been recommended as an adjuvant in HIV/AIDS treatment by the South African Ministry of Health, despite a lack of knowledge of its mechanism of action or potential immune toxicity. As yet, unsubstantiated data support the notion of immunostimulatory effects of SF extracts in HIV-infected patients. This was suggested by post-treatment recovery of CD4+ cells brought about by the reduction of the impact of virus-induced apoptosis. This study investigated the apoptotic effects of SF extracts on normal human lymphocytes in vitro. Initially, an acute cytotoxic profile of SF extract was formulated, from which an IC50 of 7.5 mg/mL was calculated and administered for 3 h, 6 h and 12 h to cell populations. At 12 h, SF caused a significant increase in apoptosis in the total lymphocyte population and CD4+ cells as evidenced by increased phosphatidylserine (PS) translocation, caspase-3/7 activity, and decreased ATP content. After 12 h, the SF extract initiated lymphocyte activation in both total lymphocyte and CD4+ subpopulations, indicated by a doubling of the number of cells expressing the CD69 activation marker. The apoptosis observed may thus be the result of activation-induced lymphocyte cell death (AICD). Our results are in conflict with preliminary clinical evidence which has suggested SF extracts are possibly beneficial in the treatment of HIV infection. More extensive evaluations of the effects of SF extracts on the immune system in such subjects are urgently needed.