Objective To investigate the predictive value of serum circulating tumor cells (CTC) combined with clinical features on the prognosis of breast cancer neoadjuvant therapy.Methods The clinical data of 80 breast cancer patients admitted to our hospital from April 2019 to April 2022 were retrospectively analyzed. According to the short-term prognosis of the patients, they were divided into good prognosis group (n = 30) and poor prognosis group (n = 50). The age, body mass index (BMI), menopausal status, breast feeding history, diabetes history, hypertension history, breast disease history, family history, tumor size, T stage, N stage, clinical stage, histological grade, axillary lymph node status, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), cell proliferation index Ki-67, molecular typing, CTC, and other clinical datas of the two groups were compared. The prognostic factors of breast cancer patients after neoadjuvant therapy were identified by multivariate Logistic regression analysis. Introduce inspection level α = 0.05, exclude inspection level α = 0.10. The value of serum CTC combined with clinical features in predicting the prognosis of breast cancer patients after neoadjuvant therapy was analyzed by consistency.Results The proportion of patients with ER negative, PR negative, HER-2 positive, Ki-67 high expression, HER-2 overexpression, and CTC negative in the good prognosis group were significantly higher than that in the poor prognosis group (P < 0.05). Multivariate Logistic regression analysis showed that ER negative [O^R = 3.113 (95% CI: 1.524, 6.359) ], PR negative [O^R = 3.242 (95% CI: 1.431,7.345) ], HER-2 positive [O^R = 2.756 (95% CI: 1.135, 6.692)] , KI-67 overexpression [O^R =2.895 (95% CI: 1.074, 7.804) ], molecular typing HER-2 overexpression [O^R = 2.957 (95% CI: 1.247, 7.012) ], and CTC negative [ O^R = 3.688 (95% CI: 1.752, 7.763) ] were prognostic factors of breast cancer patients after neoadjuvant therapy (P < 0.05). The sensitivity of serum CTC combined with clinical characteristics in predicting the prognosis of breast cancer patients after neoadjuvant therapy was 0.933 (95% CI: 1.611, 8.047), the specificity was 0.940 (95% CI: 1.336, 7.823), and the accuracy was 0.938 (95% CI: 1.288, 8.112).Conclusion Serum CTC combined with clinical features have good predictive value in the prognosis of breast cancer after neoadjuvant therapy.