Protothecosis is an uncommon infection due to Prototheca wickerhamii. Recently, a patient with progressive cutaneous protothecosis and an apparent defect in the ability of her polymorphonuclear neutrophils (PMNs) to kill P. wickerhamii was successfully treated. Therefore, the role of PMNs and serum opsonins in host defense against tissue invasion by this organism was evaluated. The results show that human PMNs ingested and kill P. wickerhamii. Ultrastructural studies revealed digestion of the organism by PMNs 60 min after ingestion. Optimal phagocytosis and killing of P. wickerhamii by PMNs required the presence of both specific IgG antibody and heat-labile opsonins.