To test the effect of the combination of trimethoprim-sulfamethoxazole (TMP-SMX) on hematological recovery after bone marrow transplantation, dogs were conditioned with 1,200 R total body irradiation and then infused with autologous marrow. Twenty dogs were given TMP-SMX at doses equivalent to 10, 20, or 40 mg TMP/kg/day beginning on the day of marrow infusion and continued until the granulocyte count reached 10(3)/mul; in addition, one-half of the dogs received methotrexate, 0.4 mg/kg on days 1, 3, 6, and 11 and then weekly until termination of the study. Granulocyte and platelet changes were compared to those of dogs given 1,200 R, autologous marrow infusion, and no TMP-SMX. Dogs given 10 and 20 mg TMP/kg/day had normal granulocyte and platelet recovery after irradiation. Dogs given 40 mg TMP/kg/day showed a significant delay in granulocyte recovery and mildly delayed platelet recovery. This suggests that TMP-SMX in prophylactic doses (5 mg TMP/kg/day) can be given safely to human patients immediately after allogeneic marrow transplantation and thus probably prevent even very early cases of Pneumocystis carinii pneumonia, and possibly bacterial infections as well.