Cutaneous lupus erythematosus (CLE) is a disfiguring autoimmune skin disease. CLE has an inflammatory infiltrate rich in T cells, which are strongly implicated in tissue damage. How these cells adapt to the skin environment and promote tissue damage is unclear. We identified an inflammatory gene program in CLE skin-infiltrating T cells dependent upon hypoxia-inducible factor-1 (HIF1), a transcription factor critical for cellular and developmental responses to hypoxia and inflammation-associated signals. HIF1 inhibitors abrogated skin disease in a murine model. HIF1 inhibition is a novel CLE therapy, with topical delivery a unique option given the small size of many HIF1 inhibitors.