An ADP-ribosyltransferase from turkey erythrocytes, which catalyzes the mono(ADP-ribosylation) of guanidino compounds such as arginine and of many purified and crude cellular proteins, appears to exist both in high-activity, histone-independent and low-activity, histone-dependent forms. At low salt concentrations, the activity of the transferase with agmatine as acceptor was less than 10% that observed in the presence of 200 mM NaCl. In the absence of salts, ADP-ribosylation of agmatine was stimulated greater than 10-fold by histones, and activity approached that observed with high salt concentration; under these conditions, the histones did not serve as ADP-ribose acceptors themselves. Histone also activated the highly purified ADP-ribosyltransferase from human erythrocytes. Enzyme activity was increased in the presence of salt and was then relatively independent of histones. DNA was not required for the stimulation of ADP-ribosylation by histone; incubation of the transferase and histone with DNase did not significantly decrease enzymatic activity. Additional DNA in the assay decreased the effect of histone. The erythrocyte ADP-ribosyltransferase from diverse species thus appears to exist in two forms: one is dependent on histones for activity and one which, in the presence of salt, has high intrinsic activity and is independent of histone. The fact that the active forms of the transferase generated in the presence of salt or histone have similar catalytic activity suggests that these forms of transferase may be identical. It would appear that the enzymatic activity of transferase from different species may be controlled by histones.