Cellular oncogenes appear to be involved in the control of normal cell growth and differentiation. The abnormal activation of these genes in naturally occurring and experimentally induced cancers may have an important role in the expression of the malignant phenotype in cancer cells. Mechanisms for the activation of these genes include chromosomal translocation, point mutation, and DNA amplification. The amplification of specific oncogenes correlates with clinical prognosis in several human malignancies, including breast cancer and neuroblastoma. We examined 21 fresh-frozen human squamous cell carcinomas of the aerodigestive tract for amplification of 10 known cellular oncogenes (c-myc, N-myc, L-myc, N-ras, H-ras, K-ras, erb-B, erb-B2, raf, and int-2), using Southern blotting techniques. Eleven of 21 tumors demonstrated a two-fold to 11-fold amplification of the int-2 oncogene, one member of a family of genes related to basic fibroblast growth factor. Amplification of c-myc, a gene that codes for a DNA-binding protein involved in the regulation of cell growth, was seen in two tumors. None of the other eight genes studied were amplified in any of the tumor specimens.