Cryptococcal infection established in adult male albino rats under experimental conditions produced minimal tissue response to the infection, probably owing to the presence of cryptococcal capsular polysaccharide. Following hyaluronidase administration in the active phases of experimental cryptococcal infection, we have observed characteristic histiocytic granulomatous transformation in cerebral as well as extracerebral lesions. It is postulated that hyaluronidase depolymerizes the capsular mucopolysaccharide of Cryptococcus neoformans and causes its lysis. As a consequence, cryptococcal yeasts that are devoid of their protective capsule and exposed to the host phagocytic system evoke a granulomatous response. Possible application of hyaluronidase as an adjuvant in the therapy of cryptococcal infections needs to be assessed.