The incidence of VRE has increased dramatically and hematology-oncology patients are at high risk for acquisition of colonization and development of infection. Therefore, we performed a prospective cohort study to determine risk factors for VRE acquisition among hematology-oncology patients. Patients admitted to a single unit at Northwestern Memorial Hospital, which was predominantly comprised of patients with hematologic malignancies and recipients of hematopoietic stem cell transplants, were enrolled. Rectal or perianal swabs were obtained on hospital day 1, 4, 7 and then weekly thereafter. Data were collected by medical record review. We evaluated 155 study patients; 12 patients (7.7%) converted from VRE negative to positive. Among these 12 patients, 3 were positive on prior admissions, and 9 acquired VRE during the study. The median time to acquisition was 9 days. The median length of stay was significantly longer for patients with VRE compared to those who were VRE negative (31 vs. 6 days, P < 0.01). Patients with VRE were significantly more likely than those without VRE to have had an ICU admission within 3 months (P = 0.003), been admitted from an acute care facility (P = 0.001), or to have received amikacin (P = 0.02). Antimicrobials were commonly prescribed to all of the patients as 87% received an antimicrobial prior to their first swab. The crude mortality rate for patients with VRE was 67%. Prolonged length of stay, prior hospitalization, previous ICU admission and receipt of amikacin were risk factors associated with VRE acquisition among hematology-oncology patients. Mortality among these patients was high, due to serious underlying disease.