Infections are a major contributor to neonatal mortality and morbidity levels all over the world. OBJECTIVES: To assess clinical efficacy and cost-effectiveness of additional immunotherapy in neonates with severe infections in neonatal intensive care unit (NICU). METHODS: We observed 375 neonates (gestational age (GA) 25-41 weeks) with severe early-onset infections in NICU. Fifty-two neonates with hypogammaglobulinemia were treated with normal human immunoglobulin (NHI), 85 newborn infants with lymphopenia were treated with human interleukin 2 (HI2), 94 neonates with low mitogen-induced interferon-α production treated with interferon-α2b. A total of 144 were under standard treatment without additional immunotherapy. RESULTS: Administration of NHI resulted in reduction of NICU length of stay and mortality level in cases of septic shock - 7.1% [0.2%; 34%] vs 40% in a similar group without immunosubstitutive therapy (p<0.05). Administration of interferon-α2b reduces hospital length of stay and mortality rates (g=0.009, OR = 0.21 [0.05; 0.67], RR = 0.26 [0.07; 0.69], NNT=8 [4; 29]). Administration of HI2 reduces NICU length of stay and mortality rates from severe infection (g=0.047; OR=0.36 [0.13; 0.98]; RR=0.41 [0.17; 0.98]; NNT=9 [4; 214]). Administration of immunotherapy in early-onset neonatal infections leads to substantial cost savings up to € 168,896 per patient in case of NHI treatment, € 60,910 per patient in case of HI2 treatment and € 69, 247 per patient in case of interferon-α2b administration. CONCLUSIONS: Additional immunotherapy in early-onset neonatal infections is a cost-effective intervention that allows to reduce mortality rates and save money.