Pigmented villonodular synovitis (PVNS) is an uncommon proliferative disease of synovium. We report a 35-year-old male with diffuse form of PVNS of left knee, treated with intraarticular injection of 5 mCi of yttrium-90 (Y-90) silicate colloid consisting of two doses with a 3-month interval between them. During follow-up, the affected knee showed clinical improvement and was accompanied by a decrease of the levels of soluble interleukin-2 receptor in sera and synovial fluids (SF). When compared to osteoarthritis subjects, SF lymphocyte subsets of this case before Y-90 therapy showed a lower CD4:CD8 cell ratio and absence of suppressor inducer cells (CD4+ 2H4+). The Tc-99m pertechnetate knee uptake indexes correlated well with clinical improvement. Serial magnetic resonance imaging revealed significant change one year after Y-90 therapy. The findings of immunological assessment suggested that immunoregulatory dysfunction may be related to the pathogenesis of PVNS.