The tolerability and potential target organ toxicity of rhIL-6 administered subcutaneously (s.c.) with rhGM-CSF or rhG-CSF were investigated in healthy nonhuman primates. Fifteen Rhesus monkeys were randomized to receive one of the following five regimens: rhIL-6, rhGM-CSF, rhG-CSF, rhIL-6 and rhGM-CSF, or rhIL-6 and rhG-CSF. Each cytokine was administered s.c. once daily at 20 micrograms/kg/day for 30-31 days. Marked increases in blood leukocyte counts (predominantly neutrophils) were observed in the rhGM-CSF and rhG-CSF treatment groups, but only a mild trend toward increased WBCs was observed with rhIL-6 alone. Platelet counts increased 1.7- to 2.2-fold in the rhIL-6 and rhGM-CSF groups. All regimens were well tolerated. RhIL-6, alone or in combination with either CSF, had no significant toxic effects at the dosages tested. Minimal to moderate bone marrow hyperplasia was observed in all except rhIL-6-treated animals, which correlated well with peripheral blood increases in WBCs. RhIL-6-treated animals demonstrated increased fibrinogen concentrations and erythrocyte sedimentation rates, decreased serum albumin/globulin ratios, and increased serum alpha-2-macroglobulin concentrations. Increased synthesis of acute-phase proteins was not observed in the other groups. Combining rhIL-6 with rhGM-CSF or rhG-CSF may reduce the rhIL-6-mediated acute-phase response while maintaining the desirable hematopoietic effects of the stimulating factors.