Mycosis fungoides and its variants are a distinct entity with a variable, but well-characterized clinical course. We report on a 51-year-old patient with tumor-stage mycosis fungoides who developed several unusual features such as extensive necrosis of lymphoma lesions, granulomatous reaction, and venular thromboses while under treatment with bexarotene, vorinostat, and high-dose fenofibrate. After surgical removal of skin necroses, the patient recovered and was in complete clinical remission. Possible causal factors such as blastic transformation; hematophagic syndrome; or bacterial, fungal, or viral infection could be excluded. We hypothesize that combination of the high-dose fenofibrate (400 mg) with the retinoid X receptor ligand bexarotene and vorinostat might have induced an increased rate of apoptosis in lymphoma cells in our patient resulting in an extensive release of lymphoma antigens. Augmented antigen release along with changes in local cytokine milieu might have induced macrophage activation and granuloma formation.