Here we describe two new cases of complete deficiency of factor I (fI) in two sisters from a consanguineous Brazilian family. The eldest sibling (20‐year‐old) developed systemic lupus erythematosus (SLE) early during childhood while the youngest had been committed on several occasions owing to repeated infections although she was asymptomatic for auto‐immune diseases. We also detected lower concentrations of C3 and factor B in both sisters. Biological functions dependent on complement activation such as the production of opsonins and killing of phagocytozed micro‐organisms, chemotactic factors and haemolytic activity were all significantly reduced in both probands. Consistent with the absence of fI and low levels of fH, a deregulated production of C3b was observed by bidimensional electrophoresis in sera of both the probands.