Background: Post-mastectomy seroma is a well-known complication which may be a seat for further complications as infection and flap necrosis, or it may cause delay in the adjuvant therapy. Several methods are used now in its prevention and treatment. This opened the door for on-going evaluation of these methods as in this article. Methods: This is an interventional study aiming to define predictive factors for selecting the most appropriate treatment modality for post-mastectomy seroma. Female patients with established diagnosis of post-mastectomy seroma following modified radical mastectomy, were treated by local injection of tetracycline after the seroma fluid was aspirated, then a crepe bandage was applied over the mastectomy area. Then, after 5 days the patients were examined again for seroma re-collection and, at this time, percutaneous catheter drainage was applied. Results: Eighteen patients were submitted to this study where multiple factors were studied regarding their effect on the response gained by local tetracycline injection (and can predict its failure with the need for percutaneous catheter application) like; patient age, physical activities, comorbidities, tumour size and pathological type, total leukocytic count, serum albumin, and the volume of the amount aspirated at the first session. Both serum albumin and the volume of the amount aspirated at the first session showed significant predictive effect (p-value; 0.019, <0.00001 respectively). Conclusions: Both serum albumin and the volume of the amount aspirated at the first session are efficient predictors for deciding which treatment modality can be selected.