The clinical value of the Crithidia luciliae (CL) method for detection of antibodies to native DNA (nDNA) was assessed. Significant titers were limited almost exclusively to patients with active systemic lupus erythematosus (SLE). Evaluation of sera from patients at the onset of active lupus demonstrated elevated anti-nDNA levels in 80% of subjects with active disease and in 94% of patients with clinically evident lupus nephritis. In longitudinal studies, rising titers of anti-nDNA were invariably accompanied by exacerbation of lupus activity. These findings suggest that the CL method correlates more closely with active SLE than do other anti-DNA methods in common use and indicate that it will prove highly useful in the diagnosis and management of SLE.