Dehydroepiandrosterone (DHEA) inhibits the development of early pre-neoplastic lesions and prevents tumor development in various tissues when given to animals during the initiation/promotion stages of carcinogenesis. Our purpose was to evaluate whether DHEA can also arrest the growth and progression of late lesions, such as persistent nodules (PNs) of rat liver. Male F344 rats were subjected to initiation by diethylnitrosamine followed by selection according to the "resistant hepatocyte" (RH) protocol. Fifteen weeks after initiation, when PNs were present in the liver, the rats were fed a diet with/without 0.6% DHEA for a maximum of 15 weeks. Glucose-6-phosphate dehydrogenase (G6PD) activity was 17- to 20-fold higher in PNs than in normal liver 15-30 weeks after initiation. It significantly decreased, in both liver and PNs, 16 hr after starting DHEA feeding. Further DHEA feeding for 3-15 weeks decreased G6PD activity by 55-58% in both tissues. Eight weeks after starting DHEA, a fall in the proportion of labeled cells, after continuous contact with 3H thymidine for 7 days, was found in nodules. Treatment for 15 weeks with DHEA caused a marked decrease in the number of nodules per liver, as well as in the incidence of PNs with diameters of 3-6 and > 6 mm, respectively, while it did not affect PNs with diameters < 3 mm. Nodules showing patterns of malignant transformation were present in 40% of rats not treated with DHEA, but not in DHEA-treated rats. All of 8 surviving rats not treated with DHEA had carcinomas at the 56th week, while only 1 out of 4 surviving rats treated with DHEA had carcinoma. These data indicate that DHEA inhibits G6PD activity in rat liver and in PNs in vivo. This is associated with growth restraint of PNs and results in inhibition of their progression to malignancy.