Background: Acute viral infections of the CNS results in substantial morbidity and mortality worldwide. Specific etiologies are identified in <50% of cases and become important to find risk factors for fatal evolution and to implement interventions based upon this knowledge. Methods & Materials: We conducted a prospective analysis of patients hospitalized in a tertiary infectious diseases hospital with acute viral CNS infections between January 2014 and December 2016, to compare characteristics of patients with fatal evolution vs. patients with good outcome. Results: 296 patients (55% males, average age 31 years) were admitted. The clinical features were suggestive for aseptic meningitis (48.6% - 144 cases), encephalitis (30% - 89) and meningo-encephalitis (19.9%- 59). The etiology was confirmed in 87 (29.4%) cases. The most frequently identified etiological agents were: Enteroviruses – 26 cases (all in children), West Nile virus – 21 (all in adults), Herpesviruses - 21 and Influenza viruses – 15. We identified statistically significant risk factors for deaths (27 cases) vs. survivors (269 cases) by age (63 years vs. 14 years, p < 0.001), type of clinical features (encephalitis 51.9% vs. 27.9% and meningo-encephalitis 48.1% vs. 17.5%, p < 0.001), symptoms (coma 55.6% vs. 4.8%, confusion 66.7% vs. 18.6%, obnubilation 55.6% vs. 9.3% all with p < 0.001 and focal neurologic findings 14.8% vs. 2.2%, p = 0.008) cerebro-spinal fluid (CSF) values (high albumin level 0.87 vs. 0.51 g/l, p = 0.004 and low cells number 21.68 vs. 178.57 cells/cubic mm, p = 0.001), blood tests (high levels of erythrocyte sedimentation rate, C reactive protein, creatinine, p < 0.001, alanine aminotransferase, p = 0.002, glucose, p = 0.001). West Nile virus (25.9% vs 5.2%) and herpesviruses (22% vs. 5.6%) are more frequent in fatal outcome group. On multivariable analysis using logistic regression only older age and coma remained statistically significant. Conclusion: CNS involvement is common during viral infections, but evolution is more severe in older age patients with encephalitis or meningo-encephalitis, high levels of CSF albumin and low levels of CSF cells. West-Nile virus and herpesviruses remain the most important etiologies associated with fatal outcome.