We compared the incidence of Her-2/neu amplification in patients with and without a family history of breast cancer and correlated gene status with clinicobiologic and prognostic features in sporadic and familial cases. Of 108 patients, 28.7% had gene amplification. Among 96 cases with family history information available, 28 had an affected first-degree relative. The gene was amplified more frequently in familial than in sporadic cases (13/28 [46%] vs 14/68 [21%]; P = .01). Among familial cases, amplification was associated with adverse clinicobiologic features (poorly differentiated tumors [P = .05], larger tumors [P = .05], more lymph nodes involved [P = .04], and DNA aneuploid [P = .02] and highly proliferative tumors [P = .005]), and the relapse (P = .02) and disease-related death (P = .05) rates were higher than in cases without amplification. Among sporadic cases, amplification was not associated with significantly different disease features, except for a higher incidence of DNA aneuploid tumors (P = .01), percentage of S-phase tumor cells (P = .006), and lower proportion of estrogen (P = .001) and progesterone (P = .002) receptors. Her-2/neu amplification was observed more frequently among patients with a family history of breast cancer, in whom it was associated with adverse clinicobiologic features and a worse clinical outcome.