Brain abscess formation was studied experimentally in rats to determine the effect and the mechanism of hyaluronidase action in the treatment of brain abscess by applying different combinations of hyaluronidase, Mycobacterium bovis (BCG), ascorbic acid and antibiotic sensitive to the inoculated bacteria in various stages of classical abscess development. The results showed that combined therapy with antibiotic and hyaluronidase started the day before inoculation a bacteria averted the formation of brain abscess and the same therapy started after encapsulation, effectively eliminated the organism and resolved the infection leaving a glial scar. But this therapy, only started at the cerebritis stages, caused an increase of cerebritis. We suggest that it is possible that hyaluronidase may act in a manner similar to its local action, and additionally may activate the immune system. Therefore, the concept of management with hyaluronidase and appropriate antibiotics might be a promising and effective chemotherapeutic method in encapsulated brain abscess for selected high-risk patients.