Several case studies have reported on neurological complications caused by a primary Epstein-Barr virus (EBV) infection. We aimed to investigate the viral loads and the clinical and inflammatory characteristics of this disease entity. We evaluated all 84 cases in which the EBV polymerase chain reaction test (PCR) was requested on cerebrospinal fluid (CSF) for the period 2003-2008. Fourteen patients with proven neuroborreliosis served as the control group. Nine patients were diagnosed with a primary EBV infection and neurological symptoms (median age 36 y; 4 male). Viral DNA copies in CSF were detected by PCR in 7 of 9 patients. The presenting symptoms were meningeal signs, epileptic insults, polyradiculomyelitis, polyradiculitis, and/or sudden cognitive disorders. All EBV cases had a pleocytosis with significantly increased mononuclear leukocytes as compared to the neuroborreliosis group (median 99% interquartile range (96-100%) versus 90% (86-97%). In cases with a primary EBV infection, viral loads ranged from 43 to 3202 copies/ml in CSF and from 61 to 15,595 copies/ml in serum. Seventy-eight percent of the cases had a positive PCR on CSF. This study provides criteria for diagnosing neurological disease during primary EBV infection. Primary EBV infections in immune competent persons can cause a broad range of neurological symptoms, with lymphocytic and monocytic inflammation both in blood and CSF.