Effects of ethanol- and phenobarbital(PB)-treatment on the metabolism of benzene in vitro and in vivo, and on the benzene-induced hemotoxicity, were investigated. Ethanol consumption markedly enhanced in vitro metabolism of both benzene and phenol in rat liver, whereas PB-treatment, which enhanced the metabolism of phenol to some degree (about one-third of ethanol-induced enhancement), did not affect the metabolism of benzene. In a single exposure experiment with rats, ethanol increased benzene metabolism in vivo as evidenced by accelerated disappearance of benzene from the blood as well as by elevated urinary excretion of phenol, whereas PB produced little or no significant influence on the metabolism. In a 3-week exposure experiment, ethanol administration accelerated benzene disappearance from the blood in agreement with the single exposure experiment, but it tended to decrease urinary phenol excretion with repetition of exposure, probably due to concomitant stimulation of subsequent phenol metabolism by ethanol. Again, PB-treatment produced only a negligible effect on the metabolism of benzene. Ethanol consumption aggravated benzene-induced hemopoietic disorder as evidenced by a marked decrease in the peripheral white blood cell number. PB produced a protective effect on the toxicity. It is concluded that ethanol potentiates benzene toxicity by accelerating (1) hydroxylation of benzene, a rate-limiting step of benzene metabolism and (2) transformation of phenol into highly toxic metabolites.