Primary effusion lymphoma (PEL) is a human herpesvirus 8 (HHV8) associated lymphoproliferative disease characterized by effusions in body cavities, and lack of tumor mass. Valganciclovir is a treatment option in PEL, however, little is known about its clinical efficacy. Ganciclovir has been reported to be effective in HHV8(+) multicentric Castleman's disease (MCD) by decreasing the plasma HHV8 load, which is an important factor in the induction and persistence of MCD, Kaposi's sarcoma (KS), and PEL. But there is no information about the efficacy of valganciclovir on HHV8 associated lymphoproliferative diseases. Here, we present the first EBV and HIV negative, HHV8 positive PEL case treated with valganciclovir; for whom it initially reduced the viral load leading to a transient partial improvement in the clinical status, but failed to induce a complete and durable remission.