We investigated the efficacy and safety of subcutaneous recombinant human erythropoietin (rHuEpo) in 25 children with chronic renal allograft dysfunction (13 girls, 12 boys, mean age 15.8 +/- 4.2 years) for a treatment period of 9-162 (median 43) weeks. rHuEpo was started once weekly at a dose of 105 +/- 25 U/kg per week in 16 children, twice weekly at a dose of 175 +/- 70 U/kg per week in 6 children, and three times weekly at a dose of 270 +/- 28 U/kg per week in 3 children. The hematocrit increased in 21 children from 23.2% +/- 3.1% to 33% +/- 3.1% within 7.2 +/- 4.9 weeks at a mean rate of 1.98%/week. The hematocrit increase and rHuEpo starting dose were linearly related (delta hematocrit/week = 0.8+0.08 U/kg per week, r = 0.44, P < 0.05). The maintenance dose was 74 +/- 23 (43-114) U/kg per week. Four children failed to reach the target hematocrit, most likely due to noncompliance. Seventeen recurrences of anemia ("anemic episodes") during rHuEpo therapy were identified in 12 children, mostly associated with acute or insidious deteriorations in graft function. There was no acceleration of progression of graft dysfunction with rHuEpo treatment. We conclude that subcutaneous rHuEpo at a single weekly dose of 100 IU/kg per week is highly effective in children with chronic graft dysfunction. Children who appear to be rHuEpo resistant or experience rHuEpo-resistant episodes should be assessed for noncompliance, changes in graft function since the last dosage adjustment, and blood loss, such as seen in dysfunctional uterine bleeding in adolescent girls.