The immune response of adult rabbits to low concentrations of BSA in their drinking water has been a useful model to study systemic immunity initiated in gut-associated lymphoid tissue. In the present study, this model was applied to neonatal rabbits. 21 New Zealand white neonatal rabbits were fed a cow-milk formula containing 0.17% BSA from the 5th to the 32nd day of life. At this time, anti-BSA was detected in only 5 animals. A subsequent intravenous injection of 50 mg BSA demonstrated a weak anti-BSA response in 6 and complete tolerance in 15 animals. Specificity of this tolerance was demonstrated by a vigorous response to 100 mg HSA, given at 60 days of age, in all of 9 animals tested. At 8 months of age, 2 of 3 animals still failed to respond to intravenous BSA, one rabbit had a low primary-type response. Determination of absorbed antigenic BSA on day 32 showed a mean of 1.09 +/- 0.47 (S.E.) microgram BSA per ml of serum, i.e. a considerably higher concentration than seen in adult animals fed similar antigen concentrations. These observations suggest that orally induced tolerance in neonatal rabbits may be due to an effect on systemic lymphoid tissue following increased antigen absorption rather than a direct antigen effect on gut-associated lymphoid tissue.