It has been speculated that symptomatic seroma, or seroma requiring needle aspiration, is one of the risk factors for lymphedema symptoms following breast cancer treatment. These symptoms exert tremendous impact on patients' quality of life and include arm swelling, chest/breast swelling, heaviness, tightness, firmness, pain, numbness, stiffness, or impaired limb mobility. Our aim was to explore if symptomatic seroma affects lymphedema symptoms following breast cancer treatment. Data were collected from 130 patients using a Demographic and Medical Information interview tool, Lymphedema and Breast Cancer Questionnaire, and review of medical record. Arm swelling was verified by Sequential Circumferential Arm Measurements and Bioelectrical Impedance Spectroscopy. Data analysis included descriptive statistics, Chi-squared tests, regression, exploratory factor analysis and exploratory structural equation modeling. Thirty-five patients (27%) developed symptomatic seroma. Locations of seroma included axilla, breast, and upper chest. Significantly, more women with seroma experienced more lymphedema symptoms. A well-fit exploratory structural equation model [X2(79) = 92.15, p = 0.148; CFI = 0.97; TLI = 0.96] revealed a significant unique effect of seroma on lymphedema symptoms of arm swelling, chest/breast swelling, tenderness, and blistering (beta = 0.48, p < 0.01). Patients who developed symptomatic seroma had 7.78 and 10.64 times the odds of developing arm swelling and chest/breast swelling versus those who did not, respectively (p < 0.001). Symptomatic seroma is associated with increased risk of developing lymphedema symptoms following breast cancer treatment. Patients who develop symptomatic seroma should be considered at higher risk for lymphedema symptoms and receive lymphedema risk reduction interventions.