Treatment with rituximab is highly effective for EBV-associated post transplant lymphoproliferative disease. However, little is known about its immunological sequelae in pediatric allogeneic hematopoietic SCT (HSCT). Time to normal CD19+ B-lymphocyte values in blood and intravenous immunoglobulin (IVIG) substitution needed to maintain an IgG>400 mg per 100 ml in six consecutive pediatric allogeneic HSCT patients treated with rituximab for symptomatic EBV reactivation were compared with a matched cohort of non-rituximab-treated patients. Follow-up of the six patients ranged from 149 to 1546 days; all but one survived. The mean (+/-s.d.) time to recovery of CD19+ B-lymphocytes was 353+/-142 days as compared with 139+/-42 in the controls (P<0.01). Similarly, substitution of IVIG as a measure of functional B-cell recovery was extended from a mean of 122+/-45 to a mean of 647+/-320 days, and the cumulative dose of IVIG increased from a mean of 1.86+/-0.51 to 4.4+/-0.97 g/kg, respectively (P<0.05). One patient had functional B-lymphocyte deficiency for >3 years and ultimately required two stem cell boosts. Rituximab is a live-saving treatment for pediatric HSCT patients but may lead to prolonged and even persistent B-cell deficiency.