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BACKGROUND: Neonates with hemolytic disease of the fetus and newborn (HDFN) may require exchange transfusions (ET) for severe hyperbilirubinemia. We evaluated if ET in neonates with HDFN was associated with the maximum maternal titer and antibody-dependent cellular cytotoxicity (ADCC) and we determined the change in the number of hospitals performing ET in the Netherlands. STUDY DESIGN AND METHODS: National, multicenter analysis of neonates for whom an ET product (c.q. reconstituted whole blood) was ordered between Jan 1, 2011 and Dec 31, 2021 in the Netherlands. To quantify the ET risk, we retrieved maternal serological test results for cases with an ET for non-ABO HDFN (numerator) and from all alloimmunized pregnancies (denominator). Current and past ET practices were assessed with a questionnaire. RESULTS: Twenty-four participating centers ordered 1564 of the total 1824 (84%) ET products in the 11-year study period. We identified 627 patients for whom a product was ordered, among these 111 (17.7%) received ET for HDFN. We found increasing ET rates in D-mediated HDFN from 0.9% (5/558) when maximum titers were ≤ 1:32 to 19.6% (18/92) if titers were 1:512. Rates of ET increased from 1.1% (9/823) if the maximum ADCC was <50% to 18.7% (72/386) if the ADCC was ≥50%. The number of hospitals practicing ET nowadays was 36.7% (18/49), a 56.1% decline compared to before 2010 (41/49). DISCUSSION: Antenatal serological tests may aid caregivers to anticipate the need for ET in neonates with non-ABO HDFN. We found a substantially altered treatment landscape with considerably fewer Dutch hospitals performing ET.