Ruxolitinib is an oral selective Janus-associated kinase 1 (JAK1) and JAK2 inhibitor that was initially approved by the FDA in 2014 for treatment of myelofibrosis. In preclinical and retrospective clinical studies, use of ruxolitinib was shown to reduce graft-versus-host-disease (GVHD) in allograft recipients with moderate/severe corticosteroid-dependent or refractory chronic GVHD. While the exact mechanism for action in GVHD is not yet fully understood, prospective studies are ongoing and some patients are receiving ruxolitinib in the setting of steroid refractory GVHD. Although ruxolitinib is generally well tolerated, here we describe a case involving a 50-year-old man with acute myeloid leukemia and chronic GVHD who experienced life-threatening hypertriglyceridemia associated with concomitant use of sirolimus and ruxolitinib for GVHD. This case report highlights the importance of vigilance for severe side effects in novel immunosuppressive drug combinations.