The effect of a combined treatment with radiation and N-nitrosoethylurea (NEU), or a split administration of NEU in inducing lymphoma was studied in female C57BL/6N mice. A single intragastric administration of 5 mg of NEU was only slightly lymphomagenic, inducing thymic lymphomas in 20% of mice, while the incidence was elevated to 92% if the NEU treatment was preceded (by 5 days) by 400 rad of total-body X-irradiation, which alone is seldom lymphomagenic. A high yield of lymphoma (84-93%) was also obtained if 5 mg of NEU was delivered in two split doses of 4 mg and 1 mg with a 4 day interval. Drastic injury to both the thymus and bone marrow caused by either 400 rad total-body X-irradiation or the first dose of NEU (4 mg) was followed by a vigorous regeneration within a few days. The maximum induction rate of lymphoma was obtained when the subsequent dose of NEU (1 mg) was given at the peak of DNA synthesis in the bone marrow and thymus following the first treatment. The data indicate that the principal effect of the irradiation or the first dose of NEU was to provide a susceptible cell population, and that a high yield of lymphoma was brought about through the action of the subsequent dose of NEU on a sufficient number of target cells engaged in heightened DNA synthesis.