The immunosuppressed state of transplant patients allows opportunistic pathogens such as human cytomegalovirus (HCMV) to cause severe disease. Therefore, inducing and boosting immunity against HCMV in recipients prior to organ transplantation is highly desirable, and accordingly, the development of an HCMV vaccine has been identified as a clinically relevant priority. Such vaccines need to be highly attenuated while eliciting specific and protective immune responses. We tested the concept of expressing the NKG2D ligand (NKG2D-L) ULBP2 by HCMV vaccine candidates to achieve NK cell activation, and, thereby viral attenuation. ULBP2 expression was found on HCMV-infected cells, reflecting the promotor strengths used to drive ULBP2 transgene expression. Moreover, significantly increased shedding of soluble ULBP2 (sULBP2) was detected for these mutants mirroring the surface expression levels. No negative effect of sULBP2 on NK cell function was observed. NK cells efficiently controlled viral spread, which was further increased by additional triggering of the activating receptor NKG2D. Engagement of NKG2D was also confirmed by its downregulation depending on ULBP2 surface density. Finally, expression of ULBP2 significantly enhanced NK cell cytotoxicity, which was independent of KIR-ligand mismatch as well as the presence of T cells. This NKG2D-L-based approach represents a feasible and promising strategy for HCMV vaccine development.