The Vaccine Adverse Event Reporting System (VAERS), administered by the FDA and CDC, is the U.S. system for surveillance of vaccine adverse events (AE). Acute encephalopathy age <18 months (EO < 18), age > or =18 months (EO > or = 18), encephalitis (EI), and multiple sclerosis (MS) after vaccination have been reported to VAERS, but reports often contain insufficient information to validate diagnoses. Standardized case definitions would enhance the utility of VAERS reports for AE surveillance. We developed practical case definitions for classification of VAERS reports, and three neurologists independently applied the definitions to reports submitted in 1993. Inter-observer agreement was assessed, and non-concordant classifications were reviewed in a follow-up conference call. Reports of EO < 18 (n = 8), EO > or = 18 (n = 20), EI (n = 15), and MS (n = 16) were classified as "definite" in 7% to 30% of the cases, while 26% to 51% of reports were thought to have insufficient information to make a classification. Agreement among reviewers was good to excellent, (kappa: 0.65 to 0.85) except for EO < 18 m for which it was marginal (kappa: 0.37). It is possible to develop reproducible case definitions for acute encephalopathy, encephalitis, and multiple sclerosis using a standardized approach. Application of standardized case definitions to VAERS reports documents the limited information in many reports, specifies data for supplemental collection, and indicates that VAERS reports should be cautiously interpreted. Development and application of case definitions for other adverse events reported after vaccination should enhance the value of vaccine safety databases. Published by Elsevier Science Inc.