We have analyzed the expression of 12 protooncogenes, c-Ha-ras, c-Ki-ras, N-ras, c-myc, N-myc, c-fos, c-abl, c-fes, c-fms, c-raf, c-erbB-1, and c-erbB-2, in tissues of human renal cell carcinomas and in adjacent normal kidneys. Comparative densitometry of Northern blot analyses demonstrated enhanced level of c-myc gene expression, i.e., greater than threefold increase over normal kidney tissues, in 11 of 15 (73%) of the tumors examined. Increased levels of c-erbB-1 mRNA were likewise observed in seven of 15 (47%). Interestingly, many of the tumors exhibiting elevated levels of c-erbB-1 revealed increases in c-myc mRNA levels. However, Southern blot analysis failed to detect gene amplification or rearrangement in the tumors with elevated levels of c-myc and/or c-erbB-1. Although N-ras, c-fos, and c-raf gene transcripts were detected in both malignant and normal tissues, differences in these protooncogene expressions were not found between the carcinomas and normal kidneys. Significant elevations of expression were found in one of 16 cases of each for c-Ha-ras and c-fms, whereas expression of c-Ki-ras, N-myc, c-fes, c-abl, or c-erbB-2 could not be detected in any of the tissues surveyed. These results suggest that activation of c-myc and c-erbB-1 genes may be involved in the development of human renal cell carcinomas.