The effects of caffeine on pancreatic tumorigenesis by 4-hydroxyaminoquinoline 1-oxide (4-HAQO) and on pancreatic DNA synthesis were studied in partially pancreatectomized male Wistar rats. 4-HAQO was injected i.v. as a single dose of 7 mg/kg body weight 3 days after partial pancreatectomy. Caffeine was injected s.c. every 12 h at the maximum tolerated dose (m.t.d.) of 120 mg/kg body weight, half the m.t.d., and one quarter the m.t.d. from 12 to 72 h before and 0 to 72, 72 to 132, and 0 to 132 h after 4-HAQO treatment. Post-treatment with caffeine from 0 to 132 h had a dose-dependent biphasic effect on pancreatic tumorigenesis: post-treatment with the m.t.d. of caffeine decreased the total number of nodules, whereas treatment with one quarter the m.t.d. of caffeine increased their number. Decrease in the number of nodules was also observed on post-treatment with the m.t.d. of caffeine from 0 to 72 or from 72 to 132 h. Pretreatment with the m.t.d. of caffeine had no significant effect on the number of nodules. Recovery of pancreatic DNA synthesis was slower after simultaneous treatment with the m.t.d. of caffeine and 4-HAQO than after treatment with 4-HAQO alone. The possible mechanism of the effect of caffeine on pancreatic tumorigenesis induced by 4-HAQO in rats is discussed.