The level of T cell activation is a better predictor of CD4+ T cell depletion in highly active anti-retroviral therapy (HAART)-treated patients than viral load. Artesunate is an artemisinin derivative that has an immunomodulatory effect. This study investigated whether artesunate tablet reduces T cell activation and improves immune reconstitution among patients with suboptimal immune recovery despite receiving long-term effective HAART. This was a randomized, prospective, parallel, open-label trial consisting of 45 participants whose plasma HIV load was effectively suppressed by HAART for over 18 months and who had CD4+ T cell counts of less than 300 cells/µL or an increase of less than 20% from baseline. The patients were randomized 2:1 into the artesunate group or the control group and received artesunate tablets (orally, 50 mg two times daily) combined with HAART or HAART alone, respectively. T-cell subsets, activation markers, clinical symptoms, viral load and side effects were assessed. By 48 weeks, artesunate tablet did not improve CD4+ T cell recovery or reduce the activation of T cell subsets but induced in a smaller decline in the expression of T cell activation markers among HAART-treated patients with incomplete immune responses. However, artesunate tablet did appear to reduce the level of T cell apoptosis. One subject developed moderate anaemia. Long-term use of artesunate tablet is unlikely to produce substantial clinical benefits in patients receiving HAART who exhibit an incomplete immune response.