Objective To investigate the effects of a synchronous spouse empowerment education program on self-efficacy and quality of life of breast cancer patients with a PICC line in the early stage of chemotherapy. Methods From October 2016 to October 2018, breast cancer patients who received chemotherapy through a PICC line were chronologically divided into 2 groups of 38 cases each according to the order of PICC insertion. The control group patients were given empowerment education, while for the intervention group, a synchronous empowerment education program involving the patients and their spouses was carried out. Data were collected before the intervention, before discharge, and before the second and the third chemotherapy cycles. Self-efficacy and quality of life of the two groups in the early stage of chemotherapy were compared. Results There were significant differences in the group, time, and time by group effects in self-efficacy and quality of life scores (P<0.05 for all). The self-efficacy and quality of life scores of the intervention group at different time points after intervention were significantly higher than those of the control group (P<0.05 for all). Conclusion The synchronous spouse empowerment education program helps to improve self-efficacy and quality of life in the early stage of chemotherapy in breast cancer patients with a PICC line.