F344 male and female rats were administered 1.25% o-phenylphenol (OPP) or 2% sodium o-phenylphenate (Na-OPP) in combination with 3% NaHCO3 or 1% NH4Cl for 8 weeks and changes in the urinary bladder histopathology and the urinary components were examined. Administration of OPP with NaHCO3 resulted in marked urothelial hyperplasia in the urinary bladder of male rats, the response being less pronounced in females. OPP alone exerted no proliferative effect and NaHCO3 induced only slight hyperplasia in males. Na-OPP alone induced mild hyperplastic lesions only in males, this being completely prevented by concomitant administration of NH4Cl. The findings thus demonstrated a clear correlation between hyperplastic response and reported carcinogenic potential of these treatments. Of the urinary factors examined, increases in levels of pH and sodium ion concentration were positively associated with proliferative lesions especially in males, although the findings failed to explain the sex difference. Urinary concentrations of non-conjugated forms of OPP metabolites were also not directly correlated with the development of hyperplasias. Thus, changes in individual urinary factors presumably affect urothelial proliferation in combination rather than separately. The presence of OPP metabolites, including 2-phenyl-1,4-benzoquinone, in the urine may be unimportant in the OPP urinary carcinogenesis even under conditions of alkalinuria and high sodium ion concentration.