Respiratory Syncytial Virus (RSV) lower respiratory tract infection produces significant morbidity and mortality in young children with congenital heart disease (CHD). Respiratory Syncytial Virus Immunoglobulin (RSVIG) is effective in preventing severe RSV illness in high-risk preterm infants. A 3 year prospective multicenter blinded study was undertaken to determine safety and efficacy of RSVIG as RSV prophylaxis in CHD. Children <48 months were randomized to an infusion group (I) receiving 750 mg/kg RSVIG monthly over the RSV season, or to a control group (C) receiving no RSVIG. Weekly phone surveillance, monthly visits and evaluation of RSV respiratory illness was performed by blinded personnel. Study children included 202 (I) and 214 (C). P=NS for (I) vs (C) for the following variables: mean age [9.3 mo. (I), 10.7 mo. (C)]; gender; crowding; smoke exposure and cardiac severity score but more children with cyanotic CHD were randomized to receive RSVIG [78/202 (I) vs 47/214 (C), p=0.001]. Reduction in RSV hospitalization, ICU admission and mechanical ventilation rates were not statistically significant when the entire group was analyzed. However, in infants <6 months of age at study entry, RSVIG reduced hospitalization by 57% (p=0.01). In acyanotic CHD RSVIG recipients, a trend towards reduced hospital rates and days was also observed[18% (I) vs 10% (C), p=0.06]. Surgically-related severe events (SSE) were more frequent in cyanotic CHD [22/78 (I) vs 4/47 (C), p=0.01] as were surgically-related fatalities [5 (I) vs 0 (C)]. We conclude that RSVIG is safe and should be effective in decreasing serious RSV illness in children <6 months of age with acyanotic CHD. While the increased SSE and surgically-related fatalities appeared to be unrelated to RSVIG administration, children with cyanotic CHD should not be given RSVIG until the cause for this finding has been determined.