Background <p>Neonatal herpes simplex virus (HSV) infection, primarily caused by HSV-2, carries a significant risk of severe morbidity, including neurological impairment and developmental delays, without timely diagnosis and intervention. The early identification of atypical cutaneous manifestations at birth and the prompt empirical initiation of high-dose intravenous acyclovir in suspected cases are crucial to prevent systemic dissemination and improve outcomes. Nevertheless, due to the unique neonatal immune response and limitations of current therapies, significant long-term sequelae such as chorioretinitis and global developmental delay may still develop, particularly when recommended suppressive antiviral regimens are not followed.</p> Case presentation <p>A late-preterm neonate (36+2 weeks) exhibited irregular white atrophic patches and scattered erosions on the trunk and neck at birth, which rapidly evolved into vesiculopustular lesions within hours. Cutaneous HSV-2 infection was confirmed by positive IgM serology and lesion PCR. Cerebrospinal fluid (CSF) analysis and HSV-2 PCR during the initial admission were negative. A history of paternal genital HSV late in gestation was reported. The infant received a 14-day course of high-dose intravenous acyclovir for presumed skin-eye-mouth disease, leading to cutaneous healing. Readmission occurred approximately three days post-discharge due to neurological decline. Blood culture identified Escherichia coli, while CSF showed marked hyperproteinorrachia with a CSF WBC count at the borderline/upper-limit range (20×10^6/L) rather than unequivocal pleocytosis, and an initially normal CSF glucose, without CSF microbiological confirmation of meningitis; therefore, bacterial meningitis could not be confirmed on readmission, although E. coli bacteremia with possible CNS involvement was considered and treated empirically. While repeat HSV-2 PCR from blood and CSF remained negative, high-dose acyclovir was empirically continued for 21 days, given the concern for potential CNS viral reactivation. HSV chorioretinitis was diagnosed during this admission, with subsequent funduscopy showing partial resolution of acute inflammation. By early childhood, cranial MRI revealed periventricular white-matter abnormalities, and the child manifested severe global developmental delay, later diagnosed as cerebral palsy, necessitating ongoing multidisciplinary rehabilitation.</p> Conclusion <p>This case highlights that congenital HSV-2 infection can present with atypical cutaneous findings at delivery, mandating high clinical suspicion and immediate empirical antiviral therapy. An initially negative CSF HSV PCR and benign cytochemistry do not guarantee against subsequent ocular or neurological involvement. This report emphasizes the imperative for routine ophthalmologic screening, extended intravenous therapy when dissemination cannot be ruled out, consideration of oral suppression in high-risk infants, and long-term, multidisciplinary follow-up for all neonates diagnosed with HSV infection, irrespective of the initial disease classification.</p>