We have investigated the drug resistance and gene amplification potential of NIH3T3 cells transfected with sequences coding for K-FGF, a known oncogene product, or bFGF, a non-oncogene member of the fibroblast growth factor family. Resistance to methotrexate, N-(phosphonacetyl)-L-aspartate and hydroxyurea was observed with K-fgf transfectants, due to amplification of dihydrofolate reductase, CAD or ribonucleotide reductase R2 genes, respectively. In keeping with the increase in gene amplification frequency, cells transfected with the K-fgf gene also exhibited a marked increase in CAD gene amplification rate, as determined by fluctuation analysis in the presence of N-(phosphonacetyl)-L-aspartate. Cells transfected with bFGF encoding cDNA also exhibited a significant elevation in N-(phosphonacetyl)-L-aspartate resistance, and CAD gene amplification. Treatment with suramin, which interferes with the interaction of fibroblast growth factors with their cell surface receptors, did not decrease the drug resistance properties of K-fgf transfected cells. These observations with suramin and the findings with bFGF, which lacks a conventional signal sequence for secretion, suggests that the growth factor-mediated effects on drug resistance and gene amplification occur through an intracellular as opposed to autocrine mode of action. The finding that aberrant growth factor expression regulates gene amplification opens up new possibilities for investigating intracellular mechanisms relevant to this process and also describes new functions for the altered expression of K-FGF and bFGF, which are relevant to mechanisms of malignant progression.