Background: Tumid lupus erythematosis (TLE) is a rare subtype of cutaneous lupus. Interferon (IFN) therapy has been known to induce autoimmune and injection-site reactions, but TLE has not previously been described to complicate hepatitis C (HCV) treatment. Herein are two cases of histologically-proven TLE in the context of HCV treatment with two forms of injectable IFN. Case 1: A 35 y/o woman with HCV, genotype 1a, stage 2 fibrosis, treated with Peg interferon α2 + ribavirin. 30 weeks into treatment she developed several pruritic, pink, crusted papules on the extensor surfaces of the arms, thighs, back and extensor surfaces of the shins. Right elbow punch biopsy showed dermal mucin with superficial and deep perivascular and peri-eccrine lymphocyte dominant infiltrates sparing the epidermis, consistent with TLE. She completed IFN therapy and achieved a sustained virologic response. Her TLE was treated successfully with topical Fluocinonide 0.05% (Lidex®) with residual hyperpigmented macules and papules. Prior to IFN, she had a (+) ANA >1:1280 speckled pattern, (+) dsDNA without features of SLE. Case 2: A 55 Y/O man with HCV, genotype 1a, stage 1-2 fibrosis; a prior non-responder to Peg interferon α2-a + ribavirin, retreated with consensus interferon + ribavirin. 12 weeks into treatment, he developed several painful, dull red, ulcerated plaques with central crusting at the abdominal injection site. Punch biopsies revealed superficial and deep perivascular and periappendageal lymphoplasmacytic inflammatory infiltrate sparing the epidermis with increased dermal mucin deposition, again consistent with TLE. These lesions were disabling compelling early IFN termination. Despite negative systemic auto-antibodies and topical Fluocinonide, he developed diffuse arthralgias and persistent ulcerated, nonhealing plaques. Skin lesions have since improved via systemic anti-malarial, hydroxychloroquine (Plaquenil®). Discussion: TLE is characterized clinically by erythematous, edematous, non-scarring papules or plaques usually on sunexposed skin. Histopathologically it resembles classic lupus erythematosis by superficial and deep lymphocytic inflammatory infiltrates and dermal mucin, however, there is little or no epidermal or dermo-epidermal involvement and ANA antibodies are usually negative. Although there is a single case series of “lupus-like” injection site reactions from IFN treatment of malignant melanoma and multiple sclerosis, as well as one report of “cutaneous mucinosis” complicating IFN treatment of HCV, TLE has not been previously reported as an adverse effect of HCV therapy. Gastroenterologists ought to be aware of this potential treatment-limiting dermatologic side effect.