Case History: A 67-year-old woman with pancreatic adenocarcinoma presented with photosensitivity and pruritic photodistributed annular plaques over the bilateral extensor forearms and dorsal hands after her fourth cycle of FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin). Dermatopathology showed an interface dermatitis with a cuffed perivascular lymphocytic infiltrate and dermal mucin, suggestive of lupus erythematosus. Laboratory evaluation demonstrated an antinuclear antibody level of 8.0 U, anti-Ro IgG > 8.0 U, and anti-La IgG > 8.0 U. Systemic lupus was excluded given the lack of systemic symptoms, normal renal function, and normal urine studies. She was diagnosed with subacute cutaneous lupus erythematosus (SCLE) thought to be induced by systemic fluorouracil. Treatment and Follow-up: Photoprotection was advised, and she was treated with topical steroids while receiving three additional chemotherapy cycles. The eruption progressed to involve her back and chest and pruritus worsened, prompting cessation of fluorouracil from her treatment regimen. Five weeks after discontinuation of fluorouracil and while still receiving folinic acid, irinotecan, and oxaliplatin, the cutaneous eruption and associated pruritus resolved. Discussion: Drug-induced SCLE is most commonly associated with thiazides, terbinafine, calcium channel blockers, and angiotensin-converting enzyme inhibitors. Although several reports describe capecitabine, an oral fluorouracil prodrug, causing SCLE, only two descriptions of fluorouracil-induced SCLE exist in the literature. The pathophysiology underlying SCLE caused by fluorouracil is unclear although it has been postulated that fluorouracil preferentially targets epidermal basal cells leading to increased ultraviolet light-induced damage. The presence of anti-Ro antibody may also predispose individuals to fluorouracil-associated lupus erythematosus-like eruptions. Given the widespread use of fluorouracil and its prodrugs in oncologic management, both oncologists and dermatologists should be aware of the possibility of fluorouracil-induced SCLE.