The chemopreventive efficacy of dehydroepiandrosterone (DHEA) and indomethacin (IM) alone or in combination was investigated in a rat multiorgan carcinogenesis model. These two chemicals were selected as chemopreventive agents with different functions. Animals were sequentially given five carcinogens with different organ target sites in the first 4-week initiation period. One week after its completion, the rats received 0.3% DHEA in the diet, 20 ppm IM in the drinking water, or 0.3% DHEA + 20 ppm IM until experimental week 28. DHEA enhanced hepatocarcinogenesis, but concurrent treatment with IM suppressed tumor development as compared to the DHEA group. DHEA inhibited tumor development in the thyroid, with a similar tendency observed for the small intestine. In addition, treatment with this hormone decreased occurrences of preneoplasias in the urinary bladder and seminal vesicles. Treatment with IM clearly suppressed development of preneoplasias or neoplasias in the lung and small and large intestines. In the urinary bladder, treatment with IM tended to decrease preneoplastic lesion development. Analysis of multiplicity of total tumors of any category revealed comparable values for DHEA and control groups, while the IM group showed a significant reduction. IM in combination with DHEA caused suppression as compared to DHEA alone. In a separate 8-week experiment, DHEA or IM were administered for 4 weeks after prior carcinogen application, and biochemical responses in the target organs were investigated. DHEA increased glucose-6-phosphate dehydrogenase levels in the liver but caused a decrease in the small intestine. In addition, DHEA decreased serum T4 but not T3. IM decreased prostaglandin E2 content in the small intestine. In conclusion, although DHEA or IM exert significant chemopreventive effects in multiorgans with the exception of the DHEA-treated liver case, treatment in combination did not result in amplification of their beneficial influence. Our results suggest the possible application of IM for chemoprevention in high-risk individuals, but the question of effects of DHEA in the liver must be answered before this hormone can be considered for use in humans.