We report two cases of myelodysplastic syndrome (MDS) with trisomy 8 who had periodic fever and erythema nodosum (EN). A 74-year-old man showed periodic fever and EN. A diagnosis of MDS with trisomy 8 was made, and he was successfully treated with prednisolone (PSL). A 71-year-old man presented with intermittent fever, EN, and recurrent elevation of myogenic enzymes. Despite sustained inflammation, laboratory tests showed macrocytic anemia and thrombocytopenia. Marrow aspiration showed MDS with the chromosomal abnormality trisomy 8. He was successfully treated with PSL without repeated transient fever and elevation of creatine kinase. The results of a literature review of 35 cases of MDS with trisomy 8 and Behçet's disease-like symptoms, such as EN, oral ulcer and intestinal ulcer, suggest that the disease entity of "trisomy 8 syndrome" may be considered, and that it is an important differential diagnosis of periodic fever and EN.