It has been postulated that the granulomatous reaction of the host to the schistosome egg is a major factor in the development of hepatosplenic schistosomiasis, and that if this reaction were suppressed, no overt disease would develop. With a technique of injecting viable Schistosoma mansoni eggs into the lungs of mice, the effect on granuloma formation of five immunosuppressive drugs was investigated. The drugs, consisting of a steroid (fluocinolone acetonide), an inhibitor of DNA-mediated RNA synthesis (actinomycin D), a folic-acid antagonist (methotrexate), and two purine analogues (azathioprine and thioguanine), were administered for 32 days after egg injection; all of them suppressed granuloma formation to varying degrees. Whereas the peak average diameter of the granulomata in the control animals 16 days after injection of the eggs was 260% larger than that of the eggs themselves, in the animals treated with the steroid there was only a 36% increase in diameter. When the drugs were discontinued, the granulomata tended to increase in size, but never approached the peak levels in the control animals. The effects of prolonged administration and different dosage levels were also studied with several of the drugs.