The inhaled arthroconidia of Coccidioides immitis mature to form large (30-80 micron) endosporulating spherules. Each spherule releases hundreds of endospores, taxing immunologic reserves. Polymorphonuclear neutrophils (PMNs) are prominent in the lesions of coccidioidomycosis, but their effectiveness is questionable. Arthroconidia possess an antiphagocytic surface derived from the original hyphal outer wall layer. Only 20%-30% of arthroconidia or endospores that are ingested by PMNs are killed. PMNs can digest the outer wall layer of spherules but may not induce lethal injury. Cell-mediated immunity is central to host defense. Macrophages ingest arthroconidia and endospores but may be unable to kill them unless lymphokines stimulate phagolysosomal fusion. Whether spherules can be killed by macrophages is unclear. C. immitis is stimulated directly by serum levels of estradiol and progesterone achieved in pregnant women. This, together with the depressed cell-mediated immunity of pregnancy, may account for the virulent nature of coccidioidomycosis in pregnant women.