In recent years, studies have demonstrated an association between human cytomegalovirus (HCMV) and destructive periodontal disease. It has been shown that reactivation of HCMV in periodontitis lesions may be related to progressing periodontal disease. Several possible mechanisms by which HCMV exerts periodontopathic potential have been previously proposed. These are reviewed and include the upregulation of bone resorptive cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) by active HCMV infection at the periodontitis site. This review focuses on the molecular basis of IL-1beta gene activation by HCMV immediate early (IE) gene products. A novel hypothesis is also described whereby HCMV plays a significant role in the pathogenesis of periodontal disease by the ability of its IE proteins to strongly transactivate IL-1beta gene expression. More studies are needed to further explore this hypothesis and clarify the association between HCMV and periodontitis.