Investigations were undertaken to determine effectiveness of 16,16-dimethyl prostaglandin E2 (dmPGE2) in overcoming the suppressive effects of ethanol and/or indomethacin on hepatic DNA synthesis. Adult litter mate Sprague-Dawley rats were subjected to sham operation or partial hepatectomy. Immediately after partial hepatectomy, and at 8-hr intervals for 24 hr, the rats were given: (a) ethanol with and without dmPGE2 or (b) indomethacin with and without ethanol and/or dmPGE2. DmPGE2 produced a significant increase in DNA synthesis in sham-operated (p less than 0.001) and untreated partially hepatectomized animals (p less than 0.025). Ethanol and indomethacin caused a 6- and 18-fold reduction, respectively, in hepatic DNA synthesis following partial hepatectomy. DmPGE2 overcame the inhibitory effect of ethanol (p less than 0.005) and indomethacin (p less than 0.0005) in partially hepatectomized animals. Mitoses were decreased concomitantly with ethanol and/or indomethacin-induced reduction in DNA synthesis and increased with administration of dmPGE2. It is concluded that dmPGE2 increases hepatic DNA synthesis and regeneration in normal rat liver and overcomes their inhibition when ethanol and/or indomethacin is given after partial hepatectomy. Timing of dmPGE2 administration is crucial. When given 30 min before ethanol, it completely inhibits suppression of regenerative activity; omission of this "priming" dmPGE2 dose results in only 44% of DNA synthesis obtained in control animals.