Because of inadequate sample sizes of randomized controlled trials, few immunologic interventions to treat or prevent neonatal sepsis have been reliably evaluated. International collaboration is essential in achieving timely, adequate samples to assess effects on mortality or disability-free survival reliably. Promising or possible therapeutic interventions in severe or gram-negative sepsis include exchange transfusions, pentoxifylline, and IgM-enriched intravenous immunoglobulin. Promising or possible prophylactic interventions include lactoferrin, with or without a probiotic; selenium; early curtailment of antibiotics after sterile cultures; breast milk; and earlier initiation of colostrum in high risk preterm infants. Prophylactic oral probiotics are safe and effective (P<.00001) in reducing all-cause mortality and necrotizing enterocolitis in preterm infants by over half, but do not reduce sepsis.