The specific activity (dpm/mg protein) of the acid-soluble nuclear material extracted from spleens or lymph nodes (but not other tissues) of tumor-bearing BALB/c mice was approximately twice that of the corresponding tissues from tumor-free mice of the same age and sex following i.p. injection of L-[U-14C]lysine. Autoradiography of gel electrophoretograms showed the major increases in radioactivity to be in histone H2A and histone H2B. Rabbit anti-mouse lymphocyte serum could prevent the splenic response to tumor only if the serum was given at the time of, or very soon after, the tumor transplant. Immunization with sheep red blood cells or with bovine serum albumin in adjuvant did cause an increase in specific activity of the splenic acid-soluble nuclear material, but there was little difference between samples from normal and tumor-bearing mice when the nuclei were purified before extraction. Use of adjuvant, with or without antigen, prevented the tumor-induced increase in the specific activity of the acid-soluble, histone fraction. Thus, adjuvant-induced suppressor cells were able to interfere with lysine incorporation. It was concluded that the tumor must grow within the host for this manifestation, since mice which were immune to the tumor as a result of vaccination had no increase in lysine incorporation, compared to normal, untreated mice. However, vaccinated mice which did not develop immunity had tumor growth and the associated increased splenic histone synthesis. A regulatory role is suggested for the histones H2A and H2B.