Human cytomegalovirus (HCMV) exploits the host transcription factor NF-kappaB to enhance its own replication, dissemination, and reactivation from latency. Here we report that HCMV infection activates the upstream IkappaB kinase (IKK) complex and that its catalytic IKK2 subunit is required for HCMV-induced NF-kappaB activation, as well as the replication of different HCMV strains. These results indicate that IKK2 is essential for HCMV replication and emphasize the feasibility of blocking NF-kappaB activation as a way of inhibiting infection.