CD8(+) T cell immunity is critical for protection from viral disease, such as that caused by the human immunodeficiency virus (HIV) or cytomegalovirus (CMV). It is therefore important to identify therapies that can boost antiviral immunity. The recent finding that thalidomide acts as a T cell costimulator suggested that this drug may boost antiviral CD8(+) T cell responses. In this in vitro study, in a human autologous CD8(+) T cell/dendritic cell (DC) coculture system, thalidomide and a potent thalidomide analogue were shown to enhance virus-specific CD8(+) T cell cytokine production and cytotoxic activity. The drug-enhanced antiviral activity was noted in cells from both healthy donors and persons chronically coinfected with HIV and CMV. This stimulatory effect was directed at CD8(+) T cells, and not DCs. These results suggest an application for thalidomide and the thalidomide analogue as a novel immune-adjuvant therapy in chronic viral infections.