Objective To explore the husband-and-wife relationship and the changes of spouse′s psychological response in young and middle-aged patients undergoing modified radical mastectomy for breast cancer, and to probe the influence of the 2 variables on depression of patients. Methods A total of 151 young and middle-aged patients having received modified radical mastectomy for breast cancer, as well as their husbands were enrolled in the longitudinal study.The participants were surveyed with the Self-rating Depression Scale (SDS), the Spouse Psychological Response Scale for Breast Cancer Patients, and the Quality of Relationship Inventory (QRI) at 2 weeks, 2 months and 12 months after operation. Results The patients scored 50.97±9.14, 54.60±9.35 and 47.42±8.72 points at 2 weeks, 2 months and 12 months after operation,respectively, with an incidence rate of depression at 56.29% (85 cases), 70.86% (107 cases) and 36.42% (55 cases), respectively at 3 time points (P＜0.01 for all).The spousal evasion and avoidance, response to body image change and negative emotion were risk factors of depression in patients, while intimate relationship was the protective factor (P＜0.05 for all).Pathway analysis showed that spouse′s psychological response could either directly predict patient depression, or indirectly influence patient depression by acting on intimate relationship, with significant indirect effect ［95%CI=(0.069,0.508)］. Conclusion Young and middle-aged patients undergoing modified radical mastectomy for breast cancer had various degree of depressive symptoms;intimate relationship played a partial mediating role between spouse′s psychological response and depression in patients.Attention should be directed to spouse′s psychological response and changes in intimate relationship, which could be conducive to early detection and intervention of depression in post-operative breast cancer patients, and boost rehabilitation of patients.