The prognostic significance of the three genes most frequently amplified in breast tumors was investigated by multivariate analysis in a retrospective study of 112 primary human breast cancers. These three genes, c-myc, int-2/FGF3 (a marker for the 11q13 amplicon), and c-erbB-2/neu, were amplified in 37%, 14%, and 10% of breast tumors studied, respectively. Amplification of the c-myc gene was not related to metastasis-free survival in the total population but was a discriminant prognostic indicator in premenopausal patients. Int-2/FGF3 gene amplications were good indicators of prognosis, especially in premenopausal patients, and also in lymph-node-positive and steroid-receptor-negative patients. Int-2/FGF3 amplification and progesterone receptor status together proved to be the only independent variable predictive of metastasis-free survival. The risk of relapse in the subgroup of progesterone-receptor-negative patients was 5 times greater for those with int-2/FGF3 amplification than for those without this alteration. Amplifications at the c-erbB-2/neu locus were not significantly associated with any standard prognostic indicator or with an increased risk of recurrence. These results suggest that the combined use of classical prognostic factors and molecular markers may improve prognostic value and be applicable to patients with specific tumor phenotypes.