Background: We are conducting multiple, prospective, phase II trials evaluating different HER-2/neu (HER2) peptide vaccines in the adjuvant setting to prevent breast cancer (BrCa) recurrence. E75 (HER2: 369-377) and another vaccine (X) are HLA-A2/3⁺-restricted peptides capable of stimulating CD8⁺ cytotoxic T cells with anti-HER2 tumor activity. Trastuzumab (Tz), a recombinant monoclonal anti-HER2 antibody, has been shown to reduce BrCa recurrence by 50%. We examined the sequential use of Tz and a CD8 T cell-eliciting vaccine to compare the efficacy of sequential passive and active immunization to passive immunotherapy alone. Methods: We examined patients from our E75 and vaccine X clinical trials. HLA-A2/3⁺ node positive or high-risk node negative BrCa patients with any level of HER2 expression, disease-free after standard treatments were vaccinated with E75 or X+GM-CSF (immunoadjuvant) vs. nothing (E75 trial) or GM-CSF alone (X trial). Vaccinations were given as 6 monthly intradermal inoculations. Patients receiving adjuvant Tz followed by vaccination were compared to those receiving Tz without vaccination (or GM-CSF alone). p-values were calculated using Fisher’s exact test. Results: Of 283 patients (E75=187; 108 vaccine, 79 control) (X=96; 41 vaccine, 55 control), 62 (22%) received adjuvant Tz (E75=15, X=47). Of the 62 Tz-treated patients, 32 received no vaccine, and their recurrence rate is 12.5% (4/32)—comparable with reported rates of similarly staged and treated patients. In contrast, 30 patients received either E75 (12) or X (18) + GM-CSF after completing adjuvant Tz, with a recurrence rate of 0% (0/30) (p=0.065). Overall median length of follow-up is 48 months (E75=57 mo, X=19 mo). Conclusions: BrCa patients enrolled in our phase II trials of the E75 or X peptide vaccines who received adjuvant Tz followed by vaccination with a CD8-eliciting peptide vaccine appear to have a lower recurrence rate than adjuvant Tz therapy alone. This finding suggests that the combination of passive and active HER-2/neu immunization may have better efficacy than passive immunotherapy alone and has prompted the initiation of combination clinical trials.