We present two siblings with congenital and progressive encephalopathy associated with systemic lupus erythematosus. The two brothers presented soon after birth with an encephalopathy associated with intracranial calcification (=2), intrauterine growth retardation (= 2), hepatitis (= 1) and thrombocytopenia (= 1), mimicking a congenital virus infection. Within the first year of life both children developed hypocomplementaemia and systemic lupus erythematosus (SLE), the main features of which were a discoid lupus-like rash on the hands and feet and the progressive production of high levels of autoantibodies. Both children were severely handicapped and died in early childhood from streptococcal infections. There are many causes of congenital encephalopathy with intracranial calcification. The early development of systemic lupus in these children suggested that their cerebral disease formed part of an autoimmune process. Complement levels and autoantibody profiles should be considered part of the investigation of a child with congenital infection-like syndrome, particularly when there are progressive dermatological complications.