Cryptococcus neoformans and cryptococcal surface polysaccharides influenced C5aR expression on human polymorphonuclear neutrophils (PMN). Encapsulated and acapsular strains produced dramatically different effects. Treatment of PMN with acapsular cryptococci up-regulated C5aR expression; whereas treatment with encapsulated cells suppressed C5aR expression. Glucuronoxylomannan (GXM), the principal constituent of the cryptococcal capsule, was responsible for such inhibition. Increased C5aR expression following treatment with acapsular cryptococci was accompanied by increased binding of C5a to PMN, increased superoxide production in response to stimulation with C5a, and an increased chemotactic response to C5a. Conversely, decreased C5aR expression following treatment with encapsulated cryptococci or acapsular cryptococci that had been pretreated with GXM was accompanied by decreased binding of C5a to PMN and a decreased chemotactic response to C5a. Our results raise the possibility that the down-regulation of C5aR expression by encapsulated cryptococci might alter PMN function at the site of cryptococcal infection.