Zidovudine therapy of AIDS patients has been shown to cause only transient improvements in the numbers of circulating CD4+ cells and the in vitro functional activities of cultured lymphocytes. The present studies were undertaken to determine whether prolonged zidovudine therapy enhanced reactivity in two sensitive assays of T-cell function: the ability of phytohemagglutinin (PHA)-stimulated cells to form T-cell colonies and their capacity to express receptors for the growth factor interleukin-2 (IL-2). Treated patients, studied over periods of 20-60 weeks, showed no improvement in colony formation at any time interval, even in plates supplemented with exogenous IL-2. However, mitogen-stimulated T lymphocytes showed a significant increase in the capacity to express IL-2 receptors (CD25). This enhanced expression resulted primarily from activation of the CD8+ cell subset.