As a marker of in vivo B-cell activity, urine levels of free light chain (FLC) were measured twice weekly by radioimmunassay (RIA) and correlated with disease activity over periods of 5–10 months in seven patients with systemic lupus erythematousus (SLE). In addition, RIA-measured urine albumin was used to track glomerular injury, and 1-microglobulin (1-M) levels, 28- to 32-kDa protein, provided control measurements on excretion of low-molecular-weight proteins. As controls, urine FLC levels were obtained from healthy normals and in subjects with acute pharyngitis, sickle-cell anemia, and acute sepsis or pneumonia. The control results showed that with acute sepsis/pneumonia had marked increases in urine FLC, while pharyngitis and sickle-cell controls had normal FLC levels. In SLE, active patients receiving intravenous cyclophsophamide and high-dose steroids exhibited highly increased urine FLC that fluctuated widely during therapy and fell to normal range levels with disease remission. During active SLE, urine albumin often was increased, while 1-M levels remained in normal range. In contrast to the increased FLC of active disease, inactive patients on low-dose maintenance therapy had predominantly normal FLC levels throughout the collection period. These results support our hypothesis that longitudinal levels of urine FLC can be used to track disease-related B-cell activity in SLE. Furthermore, we suggest that the urine FLC of active SLE would share LC idiotype with the clonal associated in vivo secreted Ig, and thus permit the identification of these antibodies that are targeted to the culprit immunogen(s) responsible for the pathogenesis of SLE.