Castleman’s disease (CD) is a rare lymphoproliferative disease. In clinical practice, the first-line treatment of multicentric Castleman disease (MCD) includes glucocorticoid, conventional chemotherapy, immunomodulators, and anti-IL-6. However, not all patients benefited from the first-line regimen, a subset of patients does not respond to front-line therapy and is considered to have primary refractory MCD. Thus, it is urgent to explore alternative treatments to provide new hope for the treatment of MCD. We report two cases of refractory MCD who achieved complete remission by thalidomide combined with interleukin-2 and interferon α-2b. The literature on the treatment of refractory MCD is reviewed.