In vitro studies indicate that encapsulated cryptococci are among the most powerful particulate activators of the complement system reported to date. The capsule itself is the site at which activation occurs. Activation occurs solely via the alternative complement pathway. Initiation occurs at apparently random focal sites in the capsule that expand through alternative pathway amplification to fill the capsule with C3 fragments. The C3 fragments are rapidly converted to iC3b, suggesting that phagocyte receptors for iC3b will be important in phagocytosis of the yeast. There is abundant evidence that a similar form of activation occurs in vivo during a cryptococcal infection. Cryptococcemia in humans and experimental animals is accompanied by a depletion of serum complement levels. Studies with complement deficient guinea pigs and mice indicate that the complement system plays an essential role in resistance to cryptococcosis. It is likely that the complement system contributes to host resistance by opsonization of the yeast to facilitate attachment and ingestion by phagocytic cells as well as by releasing chemotactic fragments of the complement cascade which contribute to the inflammatory response. The absence or unavailability of a functional complement system in the central nervous system may account in part for the predilection of the yeast for the brain.