Cytomegalovirus (CMV) reactivation is common in the allogeneic stem cell transplant setting but the incidence of CMV organ disease and mortality has been dramatically reduced by prophylactic or preemptive antiviral therapy. We report the case of a CMV-seropositive 46-year-old man with non-Hodgkin's lymphoma who underwent an unrelated allogeneic stem cell transplant from a CMV-seronegative HLA-matched unrelated donor. CMV encephalitis and colitis developed that was refractory to single-agent therapy. The CMV isolate demonstrated genotypic resistance to both ganciclovir and foscarnet. CMV disease was controlled by prolonged combination ganciclovir and cidofovir therapy, but severe renal dysfunction developed. Leflunomide was selected as a last resort to avoid the nephrotoxicity of cidofovir. CMV antigenemia rapidly increased following leflunomide administration, necessitating discontinuing this agent and resuming prior antiviral therapy. The pharmacokinetics of leflunomide in the setting of renal insufficiency is presented. Options for salvage therapy in refractory CMV disease in allogeneic stem cell transplant recipients are briefly reviewed.