Ten percent digestion of isolated nuclei by pancreatic deoxyribonuclease I preferentially removes globin DNA sequences from nuclei obtained from chick red blood cells but not from nuclei obtained from fibroblasts, from brain, or from a population of red blood cell precursors. Moreover, the nontranscribed ovalbumin sequences in nuclei isolated from red blood cells and fibroblasts are retained after mild deoxyribonuclease I digestion. This suggests that active genes are preferentially digested by deoxyribonuclease I. In contrast, treatment of red cell nuclei with staphylococcal nuclease results in no preferential digestion of active globin genes. When the 11S monomers obtained after staphylococcal nuclease digestion of nuclei are then digested with deoxyribonuclease I, the active globin genes are again preferentially digested. The results indicate that active genes are probably associated with histones in a subunit conformation in which the associated DNA is particularly sensitive to digestion by deoxyribonuclease I.