A role for polyomaviruses in the pathogenesis of systemic lupus erythematosus (SLE) has been suggested. BK virus (BKV) and JC virus (JCV) were demonstrated in single urine specimens from 7 (16%) of 44 and 5 (11%) of 44 patients with SLE and 0/88 and 18 (21%) of 88 matched healthy controls, respectively. During a 1-year follow-up study, episodes of polyomaviruria were detected in 16 (80%) of 20 patients, BKV in 13, and JCV in 3 patients. A group of 12 (60%) of 20 patients demonstrated persistent or recurrent polyomaviruria, BKV viruria (n=9), or JCV viruria (n=3) in 180 (70%) of 256 specimens. Polyomaviruria was not significantly associated with immunosuppressive therapy. The BKV and JCV isolates revealed predominantly stable archetypal regulatory regions over 3 years, indicating viral persistence rather than reinfection as a cause for urinary shedding. The demonstration of nondetectable viremia and stable archetypal BKV and JCV noncoding control regions during persistent viruria argue against the urinary tract as a focus for the creation of rearranged regulatory region variants.