Complement-dependent cytotoxicity (CDC) is an important antitumor mechanism of monoclonal antibodies (mAbs). However, trastuzumab, an anti-HER2 mAb, exerts only minor CDC. Overexpression of membrane-bound complement regulatory proteins (mCRPs), which suppress CDC, have been implicated in various malignant tumors. Here, we explored the predictive role of the expression levels of three mCRPs (CD55, CD59 and CD46) in the prognosis of breast cancer cases that underwent adjuvant trastuzumab treatment. We also studied the effect of mCRP downregulation on trastuzumab-induced CDC in vitro. Sixty-five HER2-positive breast cancer patients who received adjuvant therapy containing trastuzumab, were retrospectively analyzed. Levels of CD55, CD59 and CD46 expression were detected by immunohistochemistry. Chi-square test, Kaplan‑Meier survival analysis and a Cox proportional hazards model were used to analyze the association between CD55, CD59 and CD46 expression and prognosis. HER2-positive SK-Br3 and BT-474 breast cancer cells were pretreated with various drugs to reduce mCRP expression. Afterwards, trastuzumab‑mediated cytolytic effects were measured. Among the 65 patients, 46.2% had high expression of CD55, 44.6% had high expression of CD59 and 44.6% had high expression of CD46. The median follow-up duration was 47 months (range from 24 to 75 months). Patients with CD55 or CD59 overexpression had a higher relapse rate than those with low expression of CD55 (33.3 vs. 8.6%; P=0.013) or CD59 (31.0 vs. 11.1%; P=0.046). Similarly, mean disease-free survival of patients with CD55 or CD59 overexpression was significantly shorter than those with a low expression of CD55 (56 vs. 70 months; log-rank test, P=0.008) or CD59 (56 vs. 69 months; log-rank test, P=0.033). Multivariate analysis confirmed that CD55, but not CD59, was an independent risk factor of recurrence (HR=4.757; 95% CI, 0.985-22.974; P=0.05). In vitro, we found that tamoxifen inhibited both the protein and mRNA expression levels of CD55, but not CD59 or CD46 in SK-Br3 and BT-474 cells. After pretreatment of tamoxifen, trastuzumab-induced cytolysis was enhanced through CD55 downregulation. In conclusion, CD55 overexpression is an independent risk factor for recurrence in breast cancer patients receiving postoperative adjuvant therapy containing trastuzumab. Combined use of tamoxifen and trastuzumab for HER2-positive breast cancer treatment may enhance the antitumor effects of trastuzumab by elevated CDC, which warrants further study.