This study investigates the use of bispecific antibodies (scDbs) targeting the HIV-1 envelope protein (Env) and the human type III Fcγ receptor (CD16) to enhance natural killer (NK) cell-mediated elimination of HIV-1 reservoir cells. The scDbs, derived from broadly neutralizing antibodies (bNAbs) PG16 and 3BNC117, effectively activate NK cells and promote the lysis of HIV-1-infected CD4+ T cells. In vitro and ex vivo experiments demonstrated that these scDbs significantly reduced the number of HIV-1-infected cells, with the most potent effect observed when combined. In humanized mice, treatment with 3BNC117-Db led to a marked reduction in the frequency of HIV-1-infected CD4+ T cells, indicating the potential of scDbs in reducing the latent HIV-1 reservoir. The study also highlights the importance of latency reversal agents (LRAs) in conjunction with scDbs to enhance the effectiveness of NK cell-mediated clearance. While scDbs show promise, challenges such as their short half-life and potential for immune responses need to be addressed for clinical application. The findings suggest that scDbs could be valuable in both acute and chronic HIV-1 infection, particularly when used in combination with other therapies to improve the clearance of latent reservoirs.This study investigates the use of bispecific antibodies (scDbs) targeting the HIV-1 envelope protein (Env) and the human type III Fcγ receptor (CD16) to enhance natural killer (NK) cell-mediated elimination of HIV-1 reservoir cells. The scDbs, derived from broadly neutralizing antibodies (bNAbs) PG16 and 3BNC117, effectively activate NK cells and promote the lysis of HIV-1-infected CD4+ T cells. In vitro and ex vivo experiments demonstrated that these scDbs significantly reduced the number of HIV-1-infected cells, with the most potent effect observed when combined. In humanized mice, treatment with 3BNC117-Db led to a marked reduction in the frequency of HIV-1-infected CD4+ T cells, indicating the potential of scDbs in reducing the latent HIV-1 reservoir. The study also highlights the importance of latency reversal agents (LRAs) in conjunction with scDbs to enhance the effectiveness of NK cell-mediated clearance. While scDbs show promise, challenges such as their short half-life and potential for immune responses need to be addressed for clinical application. The findings suggest that scDbs could be valuable in both acute and chronic HIV-1 infection, particularly when used in combination with other therapies to improve the clearance of latent reservoirs.