The study analyzed 30 hospitalized patients with confirmed neuroinvasive West Nile virus infection in Italy, where 17 (56.7%) had a neurological phenotype and 13 (43.3%) had a septic phenotype. Median age was 77 years and comorbidities were similar between groups. Both phenotypes showed systemic inflammation, lymphocytopenia and elevated inflammatory indices. Patients with a septic phenotype had a lower mean corpuscular hemoglobin (MCH) and a lower percentage of monocytes. In the multivariable model, lower MCH remained independently associated with septic manifestation (OR 0.41, 95% CI 0.18–0.95). Routine hematological parameters can thus help in early characterization of the infection phenotype. Larger studies are needed to confirm.