The effects of complete Freund adjuvant (CFA) or Mycobacterium bovis BCG on leukopoiesis and on leukopoietic recovery from cyclophosphamide treatment in mice was studied. CFA injected subcutaneously or intraperitoneally resulted in increased blood granulocyte and monocyte counts, increased numbers of bone marrow granulocyte and mononuclear phagocyte progenitors, and increased hematopoietic colony-stimulating factor in the serum. Furthermore, the quantitative cellular response within 24 h to an induced sterile intraperitoneal inflammation (thioglycolate) was augmented by subcutaneous CFA. In mice given CFA subcutaneously, blood granulocyte counts, as well as the peritoneal granulocyte and macrophage response to intraperitoneal thioglycolate, recovered more quickly than did those of the controls after a 250-mg/kg dose of cyclophosphamide. CFA-treated mice consistently maintained blood granulocyte and monocyte counts 1.3-to 4-fold higher than those of the controls for 2 weeks while receiving 75 mg of cyclophosphamide per kg every other day. Mice pretreated with CFA intraperitoneally had higher numbers of bone marrow colony-forming units in culture and higher levels of serum colony-stimulating factor after 250-mg/kg injections of cyclophosphamide. Similarly, BCG resulted in increased bone marrow colony-forming units in culture, increased serum colony-stimulating factor, and a faster return of the peritoneal inflammatory response after cyclophosphamide injection. These results show that mycobacterial adjuvants accelerate recovery of leukopoietic functions after cyclophosphamide treatment and suggest a mechanism whereby such adjuvants afford nonspecific protection against infection in immunosuppressed mice.