We have recently demonstrated that polyomavirus BK and isolated BK double-stranded (ds)DNA have a strong potential for induction of anti-dsDNA antibodies. Here, data are presented that demonstrate that normal mice (a term used in this report for mice not predisposed to a lupus-like syndrome) of four different strains responded to both BK virus and BK dsDNA by producing transient antibodies binding preferentially to the viral dsDNA itself. These antibodies did not bind in the Crithidia luciliae assay, and did not seem to be of pathogenic significance, as neither signs of proteinuria nor immunochemical signs of glomerulonephritis developed in these mice. In contrast, 5-week-old (NZBxNZW)F1 mice developed strong and persistent anti-dsDNA antibodies in response to BK virus and BK dsDNA, with similar features to those of anti-dsDNA antibodies from individuals with systemic lupus erythematosus: they reacted strongly in the Crithidia luciliae assay and cross-reacted with viral as well as with mammalian dsDNA. Furthermore, persistent proteinuria and glomerulonephritis, with demonstrable heavy mesangial deposits of immune complexes containing IgG anti-dsDNA antibodies, developed 2--3 months earlier than in spontaneously autoimmune control mice. The relevance of these observations to a viral origin of anti-dsDNA antibodies in lupus is discussed.