Cyclosporin A (CsA), an inhibitor of T cell cytokine production, protects mice against staphylococcal enterotoxin B (SEB) intoxication. To determine whether CsA treatment would work in a species closer to humans. 4 rhesus monkeys were given 50 mg/kg CsA followed by an intratracheal challenge with approximately 6 LD50 of SEB. The CsA was not protective: one of the monkeys died and the other three had to be euthanised when they became moribund. All monkeys made IL-2, TNF, and IFN-gamma in response to SEB. In addition, there was about a 10-fold increase in ACTH levels 2 hr after SEB challenge. CsA significantly suppressed in vitro proliferation of lymphocytes from treated monkeys. Both CsA-treated monkeys and monkeys that had been challenged in a previous experiment with a lethal dose of SEB but had received no cyclosporin had pathologic changes in several organs. The most prominent changes were marked edema and leukocytic infiltration of the bronchial and bronchiolar mucosa. The CsA treatment appeared to reduce the intensity of lung inflammation, but this effect was not sufficient to protect the monkeys. The results suggest that CsA alone may not be an effective therapeutic agent for humans suffering from SEB intoxication or gram-positive septic shock.