Renal cell carcinoma is an inherently chemotherapeutically resistant neoplasm. Because of this, new drugs targeting this tumor are needed. One class of new anticancer drug targets the enzyme DNA topoisomerase I. Laboratory data indicate that cells sensitive to topo I targeting drugs contain high topo I levels. To determine whether some renal cell carcinomas contain elevated topo I and might therefore be targets of topo I active antitumor agents, we used a new immunohistochemical stain for topo I to determine the expression of the enzyme in 51 tumors of the kidney. Increased topo I expression was found in 4 of 11 (36%) grade 3 renal cell carcinomas and in 8 of 8 (100%) grade 4 renal cell carcinomas. Normal topo I expression was observed in all adenomas, oncocytomas, and grade 1 and grade 2 renal cell carcinomas. Because topo I targeted anticancer drugs are S-phase specific, topo II-alpha and MIB-1 proliferation indices also were performed. Topo II-alpha correlates well with MIB-1 (correlation coefficient = 0.96). Of the 12 tumors with elevated topo I, only 3 had topo II-alpha proliferation indices greater than 40, indicating a tumor with elevated topo I expression and a large growth fraction. We hypothesize that these tumors might be susceptible to topo I anticancer drug therapy. In addition, we found that the average topo II-alpha proliferation index of tumors from patients who died of disease was 27.4 +/- 19.8, which was statistically different from the average topo II-alpha index of 5.8 +/- 6.5 observed in tumors from patients who remained alive during our follow-up.