For a study in human challenge trials, oral administration of bovine antibodies active against enterotoxigenic Escherichia coli (ETEC) exhibited safety and efficacy against diarrhea. When challenged with the CS6-expressing B7A, the effectiveness of bovine serum immunoglobulins (BSIgG) against recombinant colonization factor CS6 or whole-cell ETEC strain B7A was evaluated. Healthy persons were given oral hyperimmune BSIgG anti-CS6, anti-B7A whole-cell destroyed, or non-hyperimmune BSIgG (placebo) in a 1:1:1 ratio before being challenged with ETEC B7A in a randomized, double-blind, placebo-controlled experiment. Volunteers began a seven-day course of immunoprophylaxis two days before the challenge. On the third day, the individuals were given 1×1010 CFUs of B7A. The participants were monitored for safety and the primary endpoint of moderate-to-severe diarrhea (MSD) was measured. A total of 59 patients were given products and were put through the ETEC test. All of the participants tolerated the BSIgG products well. When challenged, 14/20 (70%) of placebo receivers had MSD, compared to 12/19 (63%) of anti-CS6 BSIgG recipients and 7/20 (35%) of anti-B7A BSIgG recipients (P=.06). All of the groups had mild immune responses to the ETEC infection. Antibodies produced from bovine serum appear to be generally well tolerated. Antibodies generated from cattle inoculated with whole-cell B7A offered 50% protection against MSD after the B7A challenge; however, serum antibodies targeting CS6 showed no protection. The group’s lack of efficacy could be related to low CS6 surface expression on B7A, a high dosage challenge inoculum, or the use of serum-derived antibodies rather than colostrum-derived antibodies.