The intestinal absorption of dinitrophenyl-lysine (DNP-lys) was studied with a special interest on the role of the immune system in the absorption of small molecules which are recognized as nonself. [³H]-DNPlys was rapidly absorbed by ligated intestinal loops in situ via a saturable and unique route. When [³H]-DNP-lys was preincubated with the immune serum obtained from rats immunized with dinitrophenylated bovine serum albumin (DNP-BSA), the [³H]-DNP-lys absorption was depressed. The absorption of [³H]-DNP-lys in DNP-BSA-immunized rats was depressed compared to the control. The results obtained suggest that the immune system play a role in avoiding the absorption of small molecules with antigenicity.