Quantitative and qualitative changes in epidermal polyamine levels and DNA synthesis (specific activity and labeling index) after a single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), mezerein (MEZ), or ethylphenylpropiolate (EPP) in acetone were studied concomitantly in the same epidermal cell population from each treated mouse. The doses tested were 17 nmol of TPA; 1.7, 8.5, and 17 nmol of MEZ; and 20 µmol of EPP. With relatively small variations in time patterns, both the tumor promoter TPA and the mitogens MEZ and EPP caused similar sequential changes: initial inhibition of DNA synthesis; induction of l-ornithine decarboxylase activity; and subsequent peaks of putrescine levels preceding peaks in the rate of DNA synthesis. A remarkably good correlation between the molar ratio of spermidine/spermine and the increase in DNA synthesis was seen after all three of the compounds. However, in the initial period with inhibited DNA synthesis, a negative correlation between spermidine/spermine and DNA synthesis was observed after all of the treatments. TPA and MEZ induced pronounced biphasic increases in DNA synthesis, accumulation of putrescine, and the spermidine/spermine ratio, whereas EPP induced single-peaked increases in the same variables. The fluctuations in polyamine levels and DNA synthesis were associated with cohorts of partly synchronized cells passing the cell cycle multiple turns. Thus, the induction of l-ornithine decarboxylase and the polyamines does not seem to be specific for tumor promotion but merely seems to be associated with the cell kinetic events during stimulated cell proliferation. It is suggested that quantitative aspects of hyperproliferation may be essential for tumor promotion.