In a field trial carried out in 1985 in Matlab, Bangladesh, the authors evaluated whether subjects who developed Vibrio cholerae 01 infections during the first year after earlier receipt of B subunit-killed whole cell (BS-WC) or killed whole cell-only (WC) oral cholera vaccines exhibited deficient serum vibriocidal immune responses to these infections. After severe V. cholerae 01 infections (n = 70) in subjects > 5 years of age, the age group in which both vaccines were efficacious, a 6.5 geometric mean-fold rise of serum vibriocidal antibodies was observed among vaccinees, compared with an 18.6 geometric mean-fold rise in placebo-recipients (p < 0.01). Depressions of serum vibriocidal responses among vaccinees were even more marked after asymptomatic infections (n = 30): a 1.1 geometric mean-fold rise in vaccinees versus a 5.9 geometric mean-fold rise in placebo-recipients (p < 0.01). The authors conclude that subjects who failed to be protected by BS-WC and WC, despite being in the age group for which these vaccines were protective, exhibited poor immune responses even to the vigorous stimulus of natural infection. These findings raise the possibility that immune hyporesponsiveness may limit the potential efficacy attainable by cholera vaccines in populations with endemic cholera.