Objective: To evaluate the effectiveness and safety of functional axillary dissection based on lymphatic drainage (FUND) in decreasing breast cancer-related lymphedema (BCRL) events. Methods: A total of 168 eligible patients in Zhongnan Hospital of Wuhan University from July 2018 to February 2019 were randomly assigned to the FUND group or axillary lymph node dissection (ALND) group using random number table generated by SPSS. In the FUND group, methylene blue (MB) was adopted to reveal the sentinel lymph node (SLN) for all patients; 0.1 ml MB was injected into the SLNs before resection to reveal the efferent lymphatic channels and subsequent-echelon lymph node. The blue-stained lymphatic channels were mapped by bluntly dissecting along the lymphatic drainage channels from the breast to the axilla. Then, the SLNs were removed and pathologically analyzed by immediate frozen sectioning (FS); if the SLNs were positive, the blue-stained bALNs in breast lymphatic level (BLL) Ⅱ were removed and sent for immediate FS; if the blue-stained ALNs in BLL Ⅱ were confirmed negative, the tissues in BLL Ⅱ were removed'en bloc'. Clinicopathologic information for all the patients in the two groups were collected. The fixed-point circumference volume measurement method and the Norman questionnaire scoring method were used to evaluate the arm lymphedema between the two groups. Clinicopathological characteristics, incidences of arm lymphedema, locoregional recurrence, and distant metastasis between the two groups were compared. Results: The mean age were (50.3±8.0) in the FUND group and (51.1±9.0) in the ALND group. Seventy-four cases (88.1%) in the FUND group successfully underwent FUND surgery, and patients whose breast lymphatics failed to be stained blue underwent standard ALND. There was no statistically significant difference in terms of age, BMI, histological types, surgical approaches and adjunct therapy between the FUND group (n=74) and ALND group (n=84) (P>0.05). The average operation time of the FUND group and the stand ALND group were (169±15) and (123±12) min respectively (range: 145-198, 103-146 min) (P<0.001), and the number of lymph nodes removed [M (Q1, Q3)] were 8.3 (6, 15) and 12.9 (7, 18) (P=0.019). The cumulative BCRL rate, within a median follow-up of 24 months and 23 months respectively for FUND and ALND group, were 10.8% (8/74) vs 23.8% (20/84) (P=0.033) measured by fixed-point circumference volume measurement method, and was 12.2% (9/74) vs 27.4% (23/84) by Norman questionnaire (P=0.018). There were no local regional recurrence events during the follow-up period between the two groups. Conclusion: For breast cancer patients with clinically node-positive axilla or positive SLN, FUND based on lymphatic drainage was a less radical axillary surgery, with which eliminating the risk of BCRL might be achieved.