Rabbit and guinea pig antibodies to the 2,4-dinitrophenyl (DNP) group were separated into two subsets, one of which (subset 1) precipitated with 5-acetouracil-human serum albumin (5AU-HSA). The two subsets had similar affinities for DNP ligands, but only the subset that precipitated with 5AU-HSA had measurable affinity for the 5AU determinant. The precipitation of anti-DNP antibodies by 5AU-HSA was observed only in sera containing antibodies with high average affinity for the homologous (DNP) determinant; these antibodies had much lower average affinity for the 5AU determinant (10,000- to 100,000-fold less). The affinity of anti-DNP antibodies for a number of pyrimidines, purines and related compounds was also very weak as compared with that for the DNP determinant. Cross-reactions of anti-5AU antibodies, induced by immunization with 5AU-proteins, corresponded roughly to those for anti-DNP antibodies, i.e., the affinity of anti-5AU antibodies was much greater for 5AU than for DNP. In spite of the ease with which these weak cross-reactions with “strange” (i.e., structurally unrelated) ligands were demonstrated, differences in affinity of antibody for homologous and strange ligands were pronounced. Thus, anti-DNP and anti-5AU antibodies had the high level of specificity expected of antibodies in general. The results are relevant to some of the difficulties in interpreting weak binding reactions displayed by many myeloma proteins.