Recently, it has been demonstrated that disease progression during HIV infection is not determined merely by the number of HIV-specific T cells but also by their quality (J. R. Almeida, et al., J. Exp. Med. 204:2473-2485, 2007; C. T. Berger, et al., J. Virol. 85:9334-9345, 2011; M. R. Betts, et al., Blood 107:4781-4789, 2006; V. V. Ganusov, et al., J. Virol. 85:10518-10528, 2011; P. Kiepiela, et al., Nat. Med. 13:46-53, 2007; and F. Pereyra, et al., J. Infect. Dis. 197:563-571, 2008). Therefore, strategies to specifically enhance or induce high-quality, HIV-specific T-cell responses are necessary to develop effective immune therapies. Thalidomide, lenalidomide, and pomalidomide have a strong capacity to boost immune responses and are therefore referred to as immunomodulatory drugs (IMiDs). We evaluated the effects of lenalidomide and pomalidomide on HIV-specific T cells. We found that the presence of IMiDs during in vitro T-cell stimulation with dendritic cells electroporated with Gag- or Nef-encoding mRNA resulted in higher numbers of cytokine-secreting HIV-specific CD8(+) T cells, particularly inducing polyfunctional HIV-specific CD8(+) T cells with an enhanced lytic capacity. Furthermore, CD8(+) T-cell responses were detected upon stimulation with lower antigenic peptide concentrations, and a higher number of Gag epitopes was recognized upon addition of IMiDs. Finally, IMiDs reduced the proliferation of the HIV-specific CD4(+) T cells while increasing the number of polyfunctional CD4(+) T cells. These results provide new information about the effects of IMiDs on antigen-specific T cells and suggest that these drugs increase the efficacy of immune therapies for infectious diseases and cancer.