Two synthetic polypeptides which differ only in the order of amino acids in their NH2-terminal side chains, namely, (Tyr-Tyr-Glu-Glu)-poly(DLAla)- -poly(LLys) and (Tyr-Glu-Try-Glu)-poly(DLAla)- -poly(LLys), were found to be under different genetic control. By three different in vivo systems for thymus-derived cell depletion, it was demonstrated that (Tyr-Tyr-Glu-Glu)-poly(DLAla)- -poly(LLys), which represents the random poly(Tyr,Glu)-poly(DLAla)- -poly(Lys) in the pattern of immune responses and in the quality of antibodies they elicit, is thymus-dependent whereas (Tyr-Glu-Tyr-Glu)-poly(DLAla)-poly(LLys) does not require thymus-derived cell help for efficient antibody production. Therefore, the two ordered polypeptides which are similar chemically differ in parameters, not yet determined, which affect their capability to trigger bone marrow-derived cells.