Since both sodium L-ascorbate (Na-AsA) and sodium saccharin (Na-Sac) promote two-stage bladder carcinogenesis in rats, synergism of the two chemicals was investigated with special reference to the role of urinary pH and Na+ concentration. Male F344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 4 wk and then treated with basal diet containing 5% Na-Sac, 5% Na-AsA, 5% Na-Sac plus 5% Na-AsA, 5% L-ascorbic acid (AsA), 5% Na-Sac plus 5% AsA, or no added chemical for 32 wk. Treatment with Na-Sac or Na-AsA alone significantly increased the induction of neoplastic and preneoplastic lesions of the bladder. Na-Sac plus Na-AsA also induced these bladder lesions significantly when compared with the controls, and the number of lesions was greater than the sum of the lesions in the groups treated with Na-Sac alone or Na-AsA alone. In contrast, the induction of carcinomas and papillomas in rats treated with Na-Sac plus AsA was not significantly different from the controls. In addition Na-Sac plus Na-AsA produced an elevation of urinary pH and Na+ concentrations, although the increases were not different from those in rats fed Na-Sac or Na-AsA alone. Na-Sac plus AsA, however, did not cause elevation of urinary pH, although it increased urinary Na+ concentration. Thus, the bladder carcinogenesis promotion by Na-Sac was synergized by Na-AsA and inhibited by AsA. This modulation was associated with changes of urinary pH and Na+ concentration.