Meningoencephalitis of unknown origin (MUO) is a common inflammatory CNS disease in dogs, with a variable and unpredictable outcome. MRI and cerebrospinal fluid (CSF) features were prospectively evaluated to establish their utility as prognostic markers for predicting mortality, relapse and long-term outcome in 39 dogs with MUO. MRI and CSF analysis were performed at initial diagnosis and three months into treatment with prednisolone and cytosine arabinoside. When possible, MRI was repeated every 12 months thereafter. Median survival time was 26 days. All deaths occurred within 52 days of diagnosis (22/39; 56 per cent). One-third (13/39) died within 72 hours of diagnosis. Outcome was good or excellent in 12/17 surviving dogs. Loss of the cerebral sulci and foramen magnum herniation on MRI were associated with increased risk of mortality. An abnormal CSF analysis at the three-month re-examination was associated with increased risk of relapse (P=0.04). The combination of MRI and CSF analysis provided a greater sensitivity for predicting relapse than one modality alone. Discontinuing treatment before MRI lesions resolved always resulted in relapse. The presence of certain MRI characteristics may indicate an increased risk of mortality. Dogs alive three months following diagnosis have a very low risk of death due to MUO.