BACKGROUND: Red blood cell (RBC) alloimmunization is rarely reported in infants less than 4-6 months of age. METHODS/MATERIALS: Blood group and antibody screening used the gel card technique. All blood products were leukoreduced. All RBC doses transfused were group O, E-neg, K-neg but the pooled platelets transfused on day 45 and 61 included donors who were K-pos, and that transfused on day 61 also included an E-pos donor. RESULTS: We report a group O neonate with haemophagocytic lymphohistiocytosis (HLH) who developed alloantibodies to E and K antigens at 65 days (9 weeks) of age. CONCLUSION: HLH is an inflammatory, 'hyperimmune' state, and alloimmunization is more likely when inflammation is present. If significant inflammation is present, transfusions should be avoided if possible.