Epidemiological studies have demonstrated a correlation between regular aspirin (acetylsalicylic acid; ASA) use and a decreased risk for the development of cancer. We here show that ASA inhibits the growth of 12V-ras-transformed rat fibroblasts In vitro at pharmacological concentrations. This effect appeared to be unrelated to inhibition of cyclooxygenase, since other cyclooxygenase inhibitors did not Inhibit cell growth. A number of nuclear transcription factors have been implicated as mediators of transformation. ASA has recently been reported to inhibit the activation of one such factor, NF-kB. We found that NF-kB binding activity was decreased in ASA-treated 12V-ras-transformed cells. Inhibition of NF-kB activation was not due to a general inhibitory effect, since AP-1 binding activity was not affected. We conclude that ASA inhibits the growth of 12V-ras-transformed fibroblasts, possibly via inhibition of NF-KB.