Background: Lymphoproliferation and autoimmune cytopenias characterize autoimmune-lymphoproliferative syndrome (ALPS). Other conditions sharing these manifestations have been termed “ALPS-like”, although they are frequently more severe. Insufficient information on the genetic, clinical and immunological features of these disorders renders their diagnostic classification and treatment difficult.Methods: We performed a 14-year prospective study on 431 children referred for ALPS evaluation with lymphoproliferation and autoimmune cytopenia (n=236), lymphoproliferation and another sign of an inborn error of immunity (SoIEI) (n=148), or (bi)-autoimmune cytopenia and SoIEI (n=47). ALPS biomarkers were determined in all. Sequencing depth was recommended by the study team and IEI panel, exome or genome sequencing were performed as decided by the treating physician in 240 patients.Results: ALPS was diagnosed in 71 patients. CD38+CD45RA+ double negative T cells phenotyping did not outcompete sFASL/vitaminB12 as most predictive biomarkers. Fifty-four patients had mostly autosomal-dominant autoimmune-lymphoproliferative immunodeficiencies (AD-ALPID) affecting JAK/STAT, CTLA4/LRBA, PI3K, NFkB or RAS signaling. Sixteen patients had somatic mutations. Nineteen had other IEI, 17 other diagnoses and 79 no diagnosis despite extended genetics (ALPID-U). Multivariate clustering of clinical and laboratory manifestations did not discriminate ALPID-U from AD-ALPID, but ALPID-U patients had later onset and 80% were male. Re-classification of patients fulfilling CVID or Evans syndrome criteria did not increase the proportion of genetic diagnoses.Conclusion: The ALPID phenotype defined here is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID may be useful to direct diagnostic and therapeutic efforts also for some children currently classified as CVID or Evans syndrome.Funding: This study was supported by the Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy (CIBSS—EXC-21899—Project ID 390939984; SE), the SFB1160 (TPA08) and the BMBF-funded German Auto-Immunity Network (GAIN), grant code 197 01GM1910A (BG, SE, FH). Ales Janda was supported by ESID fellowship Program. B.G. is funded by the Deutsche Forschungsgemeinschaft (GR1617/14-1/iPAD; SFB1160/2_B5; RESIST–EXC 2155–Project ID 390874280; the EU-H2020-MSCA-COFUND EURIdoc programme (No. 101034170). Eleonora Gambinieri is funded by the Jeffrey Modell Foundation Specific Defect Research Grant (Autoimmune Cytopenias as ‘New warning sign’ of Primary Immunodeficiency Disorders). Jana Pachlopnik-Schmid received funding from the Clinical Research Priority Program CYTIMM-Z and the and the University Research Priority Program of the University of Zurich (URPP) ITINERARE – Innovative Therapies in Rare Diseases (University of Zurich, Switzerland) and the Swiss National Science Foundation grant 320030_205097 (Berne, Switzerland). Julian Knight is supported by a Wellcome Trust Investigator Award (204969/Z/16/Z) (JCK), core funding to the Wellcome Centre for Human Genetics (090532/Z/09/Z, 203141/Z/16/Z). Marco Fischer was supported by the IMM-PACT Clinician Scientist Program, Faculty of Medicine, University of Freiburg. Maria Elena Maccari is supported by the IMMediate Advanced Clinician Scientist-Program, Department of Medicine II, Medical Center – University of Freiburg and Faculty of Medicine, University of Freiburg, funded by the Bundesministerium für Bildung und Forschung (BMBF, Federal Ministry of Education and Research) - 01EO2103. Markus Seidel is funded by the Styrian Children’s Cancer Aid foundation. Michele Prioietti is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy — EXC 2155 — project number 390874280. Oliver Wegehaupt is OW is fellow of the IMM-PACT-Programme for Clinician Scientists, Department of Medicine II, Medical Center – University of Freiburg and Faculty of Medicine, University of Freiburg, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 413517907. Safa Baris is supported by a grant from Marmara University Scientific Research Project Coordination Unit (ADT-2022-10661).Declaration of Interest: Stephan Ehl and Jana Pachlopnik-Schmid are members of a DMC for Leniolisib (Pharming). Sophie Hambleton and Stephan Ehl received research funding from Pharming. Martin Armstrong is a full time employee of UCB Biopharma. Stephan Ehl received research support rom UCB for this study, including whole genome trio analysis of 30 families.Ethical Approval: The study was approved by the local IRB (No. 409⁄16). Informed consent was obtained from patients and/or their parents.