We studied the effects of etoposide on the influx, intracellular accumulation and efflux of ara-C in P388 leukemic cells. Etoposide inhibited the active influx of ara-C in a dose dependent manner, and the inhibition was reversible. Etoposide also affected the intracellular accumulation of ara-C, though its inhibitory effect for the intracellular accumulation was weaker than that for the influx of ara-C. It was also shown that etoposide inhibited the active efflux of ara-C. Furthermore, etoposide inhibited the active transport of ara-C bidirectionally but the insensitive route of etoposide existed especially at high concentration of ara-C. The effect of inhibition of the transport of ara-C on the accumulation of ara-C was more significant at lower concentration of ara-C. Judging from the drug concentrations used in this study, an interaction between etoposide and ara-C could occur in the clinical treatment.