Gamma secretase inhibition impairs HCMV replication by reduction of immediate early gene expression at the transcriptional level Due to diverse pathogenic potentials, there is a growing need for anti-HCMV agents. In this study, we show that treatment with DAPT, a γ-secretase inhibitor (GSI), impairs HCMV replication as assessed by a progeny assay based on immunostaining. This effect is not limited to DAPT because other GSIs with different structures and distinct mechanisms of action also exhibit a similar level of inhibitory effects on HCMV viral production, indicating that γ-secretase activity is required for efficient HCMV replication.