Objectives <p>This narrative review aimed to critically examine the potential impact of herpes simplex virus-1 (HSV-1) on periodontal regenerative therapy by synthesizing current evidence from in vitro studies on human periodontal ligament (PDL) cells and the limited available clinical data. Particular emphasis was placed on how HSV-1 infection alters cellular behavior and inflammatory responses in PDL cells, thereby potentially impairing periodontal regeneration.</p> Materials and methods <p>We conducted a structured literature review to identify original research articles investigating HSV-1 infection in human PDL cells and clinical studies assessing HSV infection in the context of periodontal regenerative therapy. The inclusion criteria were limited to studies that directly addressed the effects of HSV on PDL biology or regenerative outcomes.</p> Results <p>Three recent in vitro studies have demonstrated that HSV-1 infects PDL cells, inducing cytopathic effects and amplifying inflammatory cytokine production. These effects are exacerbated in pro-inflammatory microenvironments. A single clinical study suggested that HSV-1-positive patients exhibit poorer outcomes following regenerative periodontal surgery. However, the clinical evidence remains limited and exploratory in nature.</p> Conclusions <p>Although current clinical data are scarce, our in vitro findings suggest that HSV-1 compromises the regenerative potential of PDL cells through direct infection and inflammatory modulation. Further translational and longitudinal clinical studies are needed to clarify this relationship.</p> Clinical Relevance <p>Recognizing the viral influence on periodontal regeneration may help guide the future development of antiviral adjuncts and personalized regenerative strategies, especially for patients with latent HSV infections.</p>