The immunoregulatory events leading to the generation of suppressor T cells after burn injury were studied by means of a mouse burn model. Immunoresponsiveness was assessed on various postburn days with a primary in vitro mixed lymphocyte reaction (MLR). Responses of burned mice were depressed between 3 and 14 days after burn. Suppression became significant 5 days after burn and remained so through 14 days after burn. The Ly-t surface phenotype of T cells was studied on days 5 and 7 after burn. On day 5 burn, T cells responsible for suppression bore an Ly-1+,2- phenotype. By postburn day 7 suppressor T cells bore an Ly-1-,2+ phenotype. These observations are consistent with the notion of feedback suppression after burn injury, wherein Ly-1+,2- T cells induce a subset of Ly-1+,2+ T cells, thereby generating Ly-1-,2+ suppressor effector T cells. An attempt was made to uncouple the putative suppressor inducer and the suppressor effector using low doses of cyclophosphamide (CY). A single dose of 25 mg CY/kg resulted in transient restoration of depressed burn responses. By using multiple sequential doses of CY, this restorative effect could be prolonged through 8 days after burn. A dosage schedule that restores responses of burn cells without affecting responses of control cells is presented.