Chlorpromazine is a potent inhibitor of calmodulin and can alter the accumulation, metabolism, and incorporation into RNA of several fluoropyrimidine drugs. Using S-180 murine sarcoma cells, the accumulation of the base Fluorouracil and its metabolism to ribonucleotides is enhanced by chlorpromazine treatment, as measured by HPLC. In contrast, the accumulation and metabolism of the nucleoside Fluorouridine was suppressed by chlorpromazine. Cytotoxicity studies revealed that non-toxic concentrations of chlorpromazine were synergistic with Fluorouracil, but were antagonistic with Fluorouridine. These findings suggest that modulation by chlorpromazine of specific nucleoside kinase involved in Fluorouracil metabolism can result in increased therapeutic utility.