Possible correlations have been proposed between autoimmune diseases, such as systemic lupus erythematosus (SLE), and infection with human cytomegalovirus (CMV). The recent observation that an adenovirus expressing the immunodominant envelope glycoprotein of CMV, glycoprotein B (gB), may be capable of inducing autoantibodies in certain mouse strains has prompted interest in exploring potential relationships between gB immunization and autoimmune disease. We examined whether a recombinant CMV gB vaccine, or a gB canarypox vectored vaccine (ALVAC-CMVgB), administered to a total of 76 CMV-seronegative subjects, was capable of inducing cross-reactive antibodies to Smith antigen (Sm), ribonucleoprotein complex (RNP), and the U1-70 kDa component of the RNP complex. Using immunofluorescence, EIA and immunoblot analyses, we failed to identify induction of autoantibodies following vaccination with gB, whether administered alone as a purified protein subunit with adjuvant, or in combination with expression in a vectored approach using a recombinant canarypox. These data reinforce the favorable safety profile of CMV gB vaccines.