Abstract: According to the American Cancer Society, there are currently 2 million breast cancer (BC) survivors in the USA and 20% of them cope with lymphedema (LE). The primary aim of this study was to determine the predictive factors of BC-related LE. The secondary aim was to investigate the impact of predictors on the severity of LE. The study design was intended to be a 1:2 matched case–control study. Instead, we stratified on age (±10 years), radiation therapy (y/n), and type of operation (SM/MRM/MRM with tram). Patients who underwent BC surgery between 1990 and 2000 at UPMC Magee-Womens Hospital were reviewed for LE. Data were collected on 52 women with LE and 104 female controls. Logistic regression was utilized to assess the relationship between risk factors and LE. Ordinal logistic regression was performed to determine the association between risk factors and severity of LE. Severity was defined according to the volume difference between affected and unaffected limbs. Risk factors considered were occupation/hobby (hand use), TNM stage, number of dissected nodes, number of positive nodes, tumor size, infection, allergy, diabetes mellitus, hypertension, hypothyroidism, chronic obstructive pulmonary disease, and body mass index (BMI). LE was mild in 43 patients and was moderate/severe in nine patients. The level of hand use in the control group was categorized as low in 56 (54%), medium in 15 (14%), and high in 33 (32%) patients. The corresponding frequencies were 14 (33%), 6 (14%) and 23 (53%) for patients with mild LE and 3 (33%), 1 (11%), 5 (56%) for patients with moderate/severe LE (p < 0.05). Infection of the operated side arm was reported by two (2%) patients in the control group, 14 (33%) patients with mild LE and five (56%) patients with moderate/severe LE (p < 0.05). The mean BMI was 26.1 kg/m2 (SD 4.9) for the control group, 29.0 kg/m2 (SD 5.9) for the mild LE group and 30.9 kg/m2 (SD 7.5) for patients with moderate/severe LE (p < 0.05). The results of this stratified case–control study demonstrated that the risk and severity of LE was statistically related to infection, BMI, and level of hand use.