['Immunochemical therapy combining cytokines and chemotherapeutic agents is expected to be effective for treating advanced renal cell carcinoma (RCC). We investigated the mechanism underlying the synergism of interferon-alpha (IFN-alpha) and 5-fluorouracil (5-FU) and the effect of p53 status on the synergy of the combined therapy in RCC cell lines.', 'The synergy of IFN-alpha and 5-FU was analyzed by isobolographic analysis in five RCC cell lines. The effect of combined treatment on apoptosis induction was measured by flow cytometric analysis, Hoechst staining, and caspase activity assay; PCNA expression was investigated by Western blotting to examine the effect of combined treatment on the antiproliferative effect.', 'We demonstrated synergy of IFN-alpha and 5-FU in five RCC cell lines with wild-type p53. IFN-alpha suppressed the proliferation of RCC cells via G1 or G2/M cell cycle arrest without inducing apoptosis, whereas 5-FU induced apoptosis in a dosage-dependent manner. IFN-alpha enhanced the apoptosis of RCC cells induced by 5-FU, whereas 5-FU did not increase the antiproliferative effect of IFN-alpha. However, the synergistic inhibition by IFN-alpha and 5-FU was abolished when the cell lines were transfected with p53 dominant-negative vector.'] Does synergy of interferon-alpha and 5-fluorouracil in human renal cell carcinoma require p53 activity?