Lymph node enlargement is common in active systemic lupus erythematosus (SLE), a disease that is characterized by well-defined clinical criteria. Histologically, although lymphadenopathy associated with SLE exhibits marked histological diversity and occasionally shows atypical lymphoproliferative disorders, there has not been any description of the histopathological features of reactive lymph node hyperplasia with giant follicles (RHGF). We here report three such cases. The subjects were a 23-year-old Japanese female, a 44-year-old Japanese female and a 49-year-old Japanese male. All three patients initially presented with systemic lymphadenopathy. They also had systemic symptoms and abnormal laboratory findings indicating active disease, although two patients did not fulfill the diagnostic criteria for SLE at lymph node biopsy. Histologically, three lesions were characterized by numerous enlarged, coalescing lymphoid follicles with distortion rather than effacement of the lymph node architecture. By in situ hybridization, Epstein-Barr virus (EBV) genomes were demonstrated in two cases. The present three cases indicate that lymphadenopathy associated with SLE representing RFGH should be differentiated from the early stage of HIV-related lymphadenopathy as well as follicular lymphoma, particularly the floral variant. The authors would like to stress that the RHGF which is described in the present study should be listed in the pathohistology of SLE lymphadenopathy.