To determine the relationship between neoplastic transformation and increased genetic instability, spontaneous and induced mutation rates were compared in a nontumorigenic, immortalized human bronchial epithelial cell line (NL20) and a tumorigenic cell line (NL20T) spontaneously derived from the NL20 line. Using the hypoxanthine phosphoribosyltransferase (HPRT) locus as a marker for determining mutation rate, fluctuation analysis was utilized to evaluate the spontaneous mutation rate. Induced mutation rates were determined for each cell line after N-methyl-N'-nitro-N-nitrosoguanidine exposure. Both the spontaneous and induced mutation rates were noted to be significantly higher in the nontumorigenic NL20 cell line. These findings suggest that increasing genetic instability, as measured by spontaneous or induced mutation rate in the HPRT locus, does not correlate with tumorigenicity in these cells.