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We report a case of severe subacute cutaneous lupus erythematosus (SCLE) in a patient with Whipple’s disease involving the gastrointestinal and cardiac systems and chronic hepatitis B with undetectable viral load. Cutaneous lesions consistent with SCLE developed shortly after the diagnosis of Whipple’s disease, with extensive involvement of the trunk and limbs and marked photosensitivity. Histopathology revealed interface dermatitis. Direct immunofluorescence on lesional skin showed linear fibrinogen and discontinuous granular IgM deposits at the dermo-epidermal junction. Autoimmune testing demonstrated antinuclear antibody > 1:320 with a nuclear speckled and multiple nuclear dots pattern, along with anti-SSA (Ro) and anti-sp100 positivity. The patient was treated with doxycycline, high-dose hydroxychloroquine and prednisone, resulting in significant clinical improvement within 1 month.