A panel of monoclonal antibodies (MAbs) was generated against African horsesickness virus serotype 4 (AHSV/4). Three of the MAbs (SA6, OH3, and ME11) strongly neutralized the homologous virus and a heterologous type 4 isolate. The MAbs did not cross-neutralize AHS serotypes 1-3 or 5-9. The MAbs immunoprecipitated a viral protein of 108 kDa which co-migrated with VP2. Pretreatment with SA6 prevented mortality of 71% of day-old mice after intracranial injection of 100 LD50 of AHSV/4, while OH3 and ME11 significantly increased the average survival time of challenged animals. This study demonstrates that neutralizing epitope(s) for AHS are located on VP2 and that antibodies to these epitope(s) are protective in a neonatal mouse model.