Cholera epidemics are caused by <i>Vibrio cholerae</i> serogroups O1 and O139, whereas strains collectively known as non-O1/non-O139 <i>V. cholerae</i> are found in cases of extraintestinal infections and bacteremia. The mechanisms and factors influencing the occurrence of bacteremia and survival of <i>V. cholerae</i> in normal human serum have remained unclear. We found that naturally occurring IgG recognizing <i>V. cholerae</i> outer membrane protein U (OmpU) mediates a serum-killing effect in a complement C1q-dependent manner. Moreover, outer membrane vesicles (OMVs) containing OmpU caused enhanced survival of highly serum-sensitive classical <i>V. cholerae</i> in a dose-dependent manner. OMVs from wild-type and <i>ompU </i>mutant <i>V. cholerae</i> thereby provided a novel means to verify by extracellular transcomplementation the involvement of OmpU. Our data conclusively indicate that loss, or reduced expression, of OmpU imparts resistance to <i>V. cholerae</i> towards serum killing. We propose that the difference in OmpU protein levels is a plausible reason for differences in serum resistance and the ability to cause bacteremia observed among <i>V. cholerae</i> biotypes. Our findings provide a new perspective on how naturally occurring antibodies, perhaps induced by members of the microbiome, may play a role in the recognition of pathogens and the provocation of innate immune defense against bacteremia.