Ruxolitinib is a JAK1 and JAK2 inhibitor approved in 2011 for the treatment of myelofibrosis., It is unclear if this drug can increase the risk of fungal infections. We present the case of a 67-year-old man with post-polycythemia vera myelofibrosis under treatment with ruxolitinib and azacitidine admitted to the Hematology Department with a history of subacute constitutional syndrome and diarrhea followed by fever. Biopsies of oral and colonic ulcerated lesions revealed Histoplasma; and subsequent bronchoalveolar lavage (BAL) was also positive for Histoplasma and Pneumocystis. Treatment with amphotericin B and isavuconazole was initiated without discontinuing ruxolitinib, resulting in a favourable response, confirmed by PET/CT. This case highlights the potential association of invasive fungal infection (IFI) with ruxolitinib treatment, the risk of endemic opportunistic fungal infections and the usefulness of PET/CT for follow-up of disseminated IFI.