Abstract Several data indicate that HIV infection of antigen-presenting cells (APCs) and apoptosis of lymphocytcs play important roles in pathogenesis of AIDS. We have recently demonstrated that prostaglandin E2 (PGE2) can cause thymocyte apoptosis in vivo. In the present study we have investigated the possibility that the intercellular contacts between HIV-infected APCs and lymphocytes could induce apoptosis in the latter population and that PGE2-production by HIV-infected APCs could be involved in the hypothesized phenomenon. Monocytes/macrophages separated from peripheral blood mononuclear cells (PBMø) of healthy donors were infected in vitro and maintained in culture. PGE2 was promptly produced by HIV-infected PBMø and values of PGE2 concentrations in supernatants over the background noninfected controls persisted for more than 2 weeks. HIV-infected PBMø or cell-free supernatants from their cultures were then added to autologous uninfected lymphocytes and apoptosis was assessed by morphological criteria and by looking to the expression of tissue transglutaminase, one of the effector elements of the program of cell death. In both culture conditions the percentage of apoptotic lymphocytes was significantly increased in respect to values obtained in control cultures. When a cyclooxygenase inhibitor was added to the HIV-infected PBMø cultures, the percentage of apoptotic lymphocytes was reduced at levels similar to those observed after cocultivation with uninfected PBMø or exposure to supernatants from uninfected PBMø. In addition, a substantial increase in apoptosis in lymphocytes from healthy donors was found following PGE2 treatment in vitro.