Screening for antinuclear antibodies (ANA) with parallel tests for complement fixing ANA (C-ANA) reveal that C-ANA react either as strongly as or more strongly than ANA in most cases of systemic lupus erythematosus (SLE) and related disorders including CREST syndrome. But sera of drug induced LE and other ANA positive subjects have weak or no C-ANA. (P < 0.0005). Titrations with parallel C-ANA/ANA tests of two cases reveal primarily ANA and less C-ANA reactions in a case of drug induced LE but in CREST syndrome both ANA and C-ANA tests yield elevated titers with stronger C-ANA reactions. These findings point to distinct immunochemical mechanisms in C-ANA and ANA reactions.