Abstract Background Axillary lymph node dissection for staging and local control of nodal disease is an integral part of breast cancer therapy. Lymphorrea is a serious and disabling complication of axillary lymphadenectomy, but no effective therapy is currently available. Octreotide is a hormone with general antisecretory effects that has been used to control lymphorrhea in thoracic duct injury and after radical neck dissection. The aim of the study we describe in this article was to determine whether octreotide has a role in the treatment of post axillary lymphadenectomy lymphorrhea. Study design This is a prospective randomized controlled trial. Two hundred sixty-one consecutive patients with various stages of breast cancer who underwent axillary lymph node dissection were randomized and followed for 7 years. The treatment group received 0.1 mg octreotide subcutaneously three times a day for 5 days, starting on the first postoperative day, while the control group received no treatment. Of the 261 patients undergoing axillary node dissection, 136 were assigned to the control group and 125 composed the treatment group. The control group and the treatment group were evaluated for amount and duration of lymphorrhea as well as inflammatory and infectious complications. Results In the control group, the mean quantity (± standard deviation) of lymphorrhea was 94.6 ± 19 cc per day and the average duration was 16.7 ± 3.0 days. In comparison, the mean quantity of lymphorrhea in the treatment group was 65.4 ± 21.1 cc (p < 0.0001) per day and the average duration was 7.1 ± 2.9 days (p < 0.0001). We did not find an important difference in the number of infectious complication or hematomas formation between the study groups. Conclusions Octreotide can be used successfully for the treatment of post-axillary dissection lymphorrea, and potentially, in the prevention of post-axillary lymph node dissection lymphosarcoma, since the amount and duration of lymphorrhea in this setting are known to be important risk factors for its development. Potentially, octreotide might be used in similar situations where lymphorrhea is detrimental, such as peripheral vascular surgery and regional lymph node dissection for melanoma.