Escherichia coli and Bacteroides fragilis are common copathogens in clinical intra-abdominal sepsis, yet it is unclear how they interact synergistically in vivo. We sought to determine whether E. coli and B. fragilis, in combination but not alone, could exert a detrimental effect on the peritoneal host defenses of translymphatic absorption and bacterial phagocytosis. Our data indicated that noninvasive E. coli (O18ab:K56/K7:- and O111:B4), Klebsiella pneumoniae, B. fragilis, and Bacteroides thetaiotaomicron were handled in a similar fashion by both host defenses of the peritoneal cavity. The use of 2 x 108 nonviable radiolabeled E. coli as a tracer and either 2 x 109 B. fragilis or 2 x 109 E. coli (either viable or nonviable) as a competing agent to inhibit host defenses demonstrated that although clearance and phagocytosis could be inhibited, the inhibition occurred to a similar degree with either E. coli or B. fragilis. Thus, B. fragilis did not compete to any greater extent than E. coli did for peritoneal clearance or opsonization and phagocytosis in vivo. These data indicate that bacterial synergy probably does not occur on the basis of reduced peritoneal clearance or by a reduction in the opsonization and phagocytosis of either organism by the copathogen. These results provide indirect support for the hypothesis that in bacterial synergy, one organism directly stimulates the growth of the other, perhaps by providing a growth factor.