The lesions of blastomycosis are characterized by both suppuration and granuloma formation, but the relative roles of human neutrophils, monocytes, and macrophages against Blastomyces dermatitidis are poorly defined. Our studies reveal that B. dermatitidis yeasts are generally too large to be ingested by polymorphonuclear neutrophils (PMNs), and are killed predominantly by external PMN attachment and degranulation, whereas conidia are first ingested, then killed. PMN function is maximal in the presence of serum, divalent cations, and complement, and killing is more efficient for conidia (approximately 50%) than for yeasts (approximately 20%). PMNs that have degranulated, but remain attached to yeasts, block access by contiguous PMNs. When degranulated PMNs are removed, allowing access by fresh PMNs, there is a further increment in yeast killing. Both conidia and yeasts are killed by predominantly oxidative PMN mechanisms, with conidia being greater activators of the respiratory burst, and proportionately more influenced by oxidative inhibitors. Peripheral blood monocytes can kill conidia (approximately 35%), but are feebly active against yeasts (approximately 5%). Monocyte-derived macrophages kill approximately 90% of conidia and 40% of yeasts. The dramatic susceptibility of conidia, the infective particles of B. dermatitidis, to nonspecific phagocytic host defenses may help to explain the relative rarity of blastomycosis as a clinical problem. The presence of PMNs in lesions of blastomycosis may indicate an active, although limited, role of these cells in host defense against B. dermatitidis yeasts.