The effect of cortisone acetate (CA) treatment on the anticryptococcal activity by rat alveolar macrophages (AM) was investigated. The animals received a weekly dose of 5 mg CA during 1, 2, 3 or 4 weeks. Following the final dose the AM were collected by lung lavage and challenged with Cryptococcus neoformans. Parallel experiments with silica particles of a similar size were performed. The phagocytic function was assessed using a fluorescence method that distinguishes between attached and ingested particles. The oxidative metabolism was studied by the nitroblue tetrazolium (NBT) reduction test. The accumulated attachment (a measure of the attachment process) of cryptococci and silica particles per AM was significantly depressed after the third and fourth week of CA treatment. The ingested fraction (a measure of the ingestion process) of cryptococci but not of silica particles showed a small but significant decrease after the fourth week. The NBT reduction of the unstimulated AM and those stimulated with either the cryptococci or silica particles for 24 h was significantly reduced after the fourth week of treatment. In conclusion, these results demonstrate that high dose CA treatment primarily affects the attachment of the cryptococci to the AM and to a lesser extent also the ingestion process. In addition, it decreases the NBT reduction by AM in response to the yeast. The impairment of the AM anticryptococcal activity by high doses of CA constitutes a risk of dissemination of C. neoformans from the lungs.