Chronic anemia caused by HPV-B19 has been reported in HIV-infected adults. Patients have responded variably to different doses of IVIG, although most sustained responses have been achieved only with high dose (≥2 g/kg) IVIG. We studied the virologic response of HPB-B19 to two dose ranges of IVIG in a severely immune-suppressed HIV-infected child. Our three year-old Class C3 patient developed chronic transfusion-dependent anemia which was not drug-induced and not responsive to erythropoietin or steroids. When HPV-B19 IgM was reported positive and HPV was detected in her blood by PCR, she was treated with seven monthly doses of IVIG, 0.4 g/kg. She continued to require monthly transfusions, and HPV remained detectable by primary PCR. She was then treated with high-dose IVIG (1 g/kg/day × 2 consecutive days) and required no further transfusions for more than six months. With clinical recovery, primary PCR became negative but HPV remained detectable by second stage PCR (re-amplification of target DNA using primers internal to the initial PCR product). With a subsequent relapse, HPV was again detectable by primary PCR but, following re-treatment with high-dose IVIG, required second stage PCR for detection. Serum HPV IgG remained negative throughout her period of recovery. From our case and others, we conclude: 1) IVIG must be used in doses higher than standard replacement therapy to achieve a sustained hematopoietic response to HPV-B19-induced anemia in immunocompromised patients; 2) the mechanisms of IVIG in maintaining the hematopoietic response is unclear, as its effect may continue well beyond several half-lives, despite virologic evidence of persistent infection; 3) PCR is the most sensitive method to identify viral DNA, and second-stage PCR may be necessary to detect a persistent, but reduced, viral burden following IVIG; and 4) serologic and virologic HPV-B19 studies should be included in the early diagnostic evaluation of anemia in HIV-infected children.