Intranasal infection with vaccine strain of Venezuelan equine encephalitis virus (TC83) caused persistent viral infection in the brains of mice without functional a beta T-cells (a beta-TCR -/-). Remarkably, viral kinetics, host response gene transcripts and symptomatic disease are similar between a beta-TCR -/- and wild-type C57BL/6 (WT) mice during acute phase of infection [0-13 days post-infection (dpi)]. While WT mice clear infectious virus in the brain by 13 dpi, a beta-TCR -/- maintain infectious virus in the brain to 92 dpi. Persistent brain infection in a beta-TCR -/- correlated with inflammatory infiltrates and elevated cytokine protein levels in the brain at later time points. Persistent brain infection of a beta-TCR -/- mice provides a novel model to study prolonged alphaviral infection as well as the effects and biomarkers of long-term viral inflammation in the brain.