Prophylaxis with fluoroquinolones for patients undergoing autologous stem cell transplantation (ASCT) remains controversial. We performed a retrospective review of patients undergoing ASCT with and without bacterial prophylaxis to compare endpoints of interest. Per institutional policy, patients undergoing ASCT for multiple myeloma routinely receive levofloxacin prophylaxis during their period of neutropenia, while patients undergoing the same for lymphoma do not. We retrospectively examined multiple myeloma (MM) or lymphoma patients undergoing ASCT between July of 2015 and July of 2018 for evidence of positive blood cultures. In total, 172 patients underwent ASCT for lymphoma and 343 for MM. Both groups were similar with respect to baseline characteristics. Twenty percent (35/172) of patients with lymphoma and 5.2% (18/342) of patients with MM had blood stream infections. Blood stream infections (BSI) occurred in patients with lymphoma on average 2 days prior to patients with MM (d+5 vs d+7, P = 0.0003). Both groups recovered ANC by the same time. Length of stay (LOS) was 2 days shorter for patients with MM (median 20 vs 18, P = 0.01). The majority of the organisms were gram negatives in both groups. Of the organisms commonly tested for FQ sensitivity, only 1/25 in the lymphoma group was resistant compared to 7/9 in the MM group (P < 0.0001) with 4 being multidrug resistant (MDR, Table 2). Odds of developing an infection in the lymphoma group was 4.6 times the odds of developing BSI in the myeloma group [95% confidence interval (CI): 2.52-8.40, P < 0.0001]. In total, 23/172 (13.4%) patients with lymphoma and 28/342 (8.2%) patients with MM developed CDI with an OR of 1.73 (95% CI: 0.96-3.11, P = 0.066). Two infection-related deaths occurred in the MM group. Fluoroquinolone prophylaxis reduces the rate BSI in patients undergoing ASCT but increase the incidence of resistant organisms. We recommend routine antimicrobial prophylaxis in patients undergoing ASCT to reduce the risk of BSI with systematic and regular review of outcomes.