GTI-2040, an antisense oligonucleotide targeting the small subunit of ribonucleotide reductase, acts as an anti-tumor agent in animal models of human cancer. In the present study, the anti-tumor activity of GTI-2040, in combination with interferon alpha (IFNalpha) was investigated against human renal cell carcinoma tumors xenografted into mice. The human renal cell carcinoma cell lines, Caki-1 and A498 were sensitive to IFNalpha both in vitro and when implanted into mice. In combination with GTI-2040 there were cooperative effects at intermediate doses of the two agents and complete tumor regression at higher combination doses. A control oligonucleotide was not effective as a monotherapy and did not improve the efficacy of IFNalpha. The effect of combination treatment on apoptosis and proliferation of tumor cells, isolated from xenografted tumors, was examined by histochemistry. GTI-2040 increased the percentage of cells undergoing apoptosis with a concomitant decrease in proliferation. IFNalpha alone had no effect but in combination with GTI-2040 resulted in increased apoptosis and decreased proliferation compared to GTI-2040 alone. Taken together these results expand the potential clinical applications of GTI-2040 to include combination therapy with IFNalpha.