Background: Encephalitis is a serious neurological syndrome that can be caused by various infectious agents, particularly in immunocompromised individuals. Among these agents, viruses from the Herpesviridae family play a major role, although their diagnosis is often underestimated and their involvement remains poorly understood, particularly in developing countries such as those in West Africa. Aim: This cross-sectional, descriptive, multicenter study was conducted in hospitals in two regions of C？te d’Ivoire, namely Abidjan and Bouaké, between March 2024 and April 2025 to assess the prevalence of herpesviruses. Methods: CSF samples were collected from patients aged ≥ 15 years who presented with clinical signs of encephalitis and were subjected to molecular analysis. Viral DNA extraction and PCR tests were used to detect Herpes simplex virus 1 and 2 (HSV 1/2), Varicella-Zoster virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and Human herpesvirus 6 (HHV6). Clinical data and molecular analysis results were recorded using Excel software, and statistical analysis was performed using RStudio 4.2.1 software. Results are presented as mean and standard deviation for quantitative variables and as percentages for qualitative variables. Results: A total of 388 patients were included in this study (222 women and 166 men; age range 15 - 79 years; mean age 45.36 ± 13.55 years), and 60 (15.46%) were positive for one or more herpesvirus. Epstein-Barr virus was most frequently detected in 33 (55.00%) of positive cases, followed by Cytomegalovirus with 20 (33.33%) and Varicella-Zoster virus and Human herpes virus 6 with respective rates of 20.00% (12) for VZV and 11.67% (07) for HHV6. A single Herpes simplex virus (1.67%) was detected. Among the patients with a positive PCR, 10 (16.67%) were co-infected with herpesviruses. All co-infected patients were HIV seropositive. The chi-square test showed a significant association between HIV infection status and the molecular detection of herpesvirus in patients with encephalitis (OR 3.9; 95% CI: [1.4 - 9.3]; P < 0.0015). Conclusion: Herpesviruses are a significant cause of encephalitis, particularly in immunocompromised and immunocompetent patients. In our study, EBV and CMV were the most common. Therefore, the rapid identification of these viruses in the CSF and the initiation of appropriate antiviral treatment are essential to reduce mortality and improve the management of
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