A 28-year-old man developed gangrene of a foot leading to a below-the-knee amputation. Although initially diagnosed as atherosclerotic vascular disease, clinical and laboratory findings of systemic lupus erythematosus (SLE) developed over the next 18 months. Histologic review of popliteal and femoral artery specimens showed acute and chronic changes consistent with the vasculitis of SLE. Subsequent treatment with prednisone controlled the vasculitis as well as the other clinical manifestations of SLE. The diagnosis of SLE should be considered in patients with large vessel peripheral vascular disease who lack the typical findings of the more common predisposing causes.