Vaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe COVID-19, it is important to identify those patients that benefit from vaccination. We prospectively quantified serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens during and after 2-dose mRNA-1273 (Spikevax/Moderna) vaccination in hematology patients. Obtaining S1 IgG 300bindingantibodyunits(BAUs)/mLwasconsideredadequateasitrepresentsthelowerlevelofS1IgGconcentrationobtainedinhealthyindividuals,anditcorrelateswithpotentvirusneutralization.Selectedpatients(n5723)wereseverelyimmunocompromisedowingtotheirdiseaseortreatmentthereof.Nevertheless,.50 300 BAUs/mL after 2-dose mRNA-1273. All patients with sickle cell disease or chronic myeloid leukemia obtained adequate antibody concentrations. Around 70% of patients with chronic graft-versus-host disease (cGVHD), multiple myeloma, or untreated chronic lymphocytic leukemia (CLL) obtained S1 IgG 300BAUs/mL.Ruxolitiniborhypomethylatingtherapybutnothigh−dosechemotherapybluntedresponsesinmyeloidmalignancies.Responsesinpatientswithlymphoma,patientswithCLLonibrutinib,andchimericantigenreceptorT−cellrecipientswerelow.Theminimaltimeintervalafterautologoushematopoieticcelltransplantation(HCT)toreachadequateconcentrationswas,2monthsformultiplemyeloma,8monthsforlymphoma,and4to6monthsafterallogeneicHCT.SerumIgG4,absoluteB−andnaturalkiller–cellnumber,andnumberofimmunosuppressantspredictedS1IgG 300 BAUs/mL. Hematology patients on chemotherapy, shortly after HCT, or with cGVHD should not be precluded from vaccination. This trial was registered at Netherlands Trial Register as #NL9553