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Polymicrobial bloodstream infections (pBSI) occurring in hematological patients are still poorly understood, and specific information are very limited. In this epidemiologic survey, we describe clinical characteristics and outcome of 125 consecutive pBSI occurred in oncohematological patients. Polymicrobial bloodstream infections (pBSI) were defined with the isolation of 2 or more bacteria from blood culture specimens obtained within 72 h. Over an 11-year period, we documented 500 bacterial bloodstream infections (BSI) in 4542 hospital admissions and 25% (125) of these were pBSI. Most common underlying hematological disease was acute myeloid leukemia and 89% of patients had severe neutropenia. Fifty pBSI (40%) occurred in patients undergoing a stem cell transplantation (SCT), mostly within 30 days from transplant (42/50–84%). Principal bacterial association was Gram-positive plus Gram-negative (57%). Resolution rate of pBSI was 82%, without differences between SCT and non-SCT cases. pBSI-related mortality was 15% (6% in SCT cases). Septic shock occurred in 16% of cases and septic shock–related mortality was 65% (75% in SCT cases and 63% in non-SCT cases; p = 0.6). Multidrug-resistant (MDR) bacteria were involved in 22% of pBSI and the MDR-pBSI–related mortality was significantly higher in SCT patients (p = 0.007). This observational study highlights that pBSI is not a rare bloodstream infectious complication in oncohematological patients. pBSI-related mortality is lower than 20%, but, if septic shock occurs, mortality reaches 65%. MDR bacteria were involved in 22% of cases and pBSI-MDR–related mortality was significantly higher in SCT patients.