Many radiation events have involved a high incidence of radiation combined injuries. Victims of radiation events succumb to serious infections as a consequence of bacterial translocation and sepsis. Exacerbation of the risk of infection by radiation combined burn injury (RCBI) further heightens vulnerability. There are currently no suitable countermeasures that exist for RCBIs. We evaluated 2-0, 3-0 desulfated heparin (ODSH), an anti-inflammatory and anticoagulant agent as a potential countermeasure to RCBI. Female B6D2F1/J mice (12-week) were subjected to 9.5 Gy (LD70/30 for RCBI) whole-body bilateral 60Co gamma-photon radiation (0.4 Gy/min), followed by dorsal skin burn injury under anesthesia (∼15% total-body-surface area burn). Mice were injected subcutaneously with ODSH (25 mg/kg every 12 h; days 1-2 and 17.5 mg/kg every 12 h; days 3-7) or vehicle (sterile saline of equal volume) for 7 days post-injury and further administered topical gentamicin (0.1% cream; days 1-10) and oral levofloxacin (100 mg/kg; days 3-16). Mice were euthanized on day 30 following water consumption, body mass and survival analysis. Our data showed ODSH had no effect on radiation injury (RI)-induced mortality (45% ODSH vs. 45% VEH; n=20). However interestingly, ODSH treatment significantly reduced survival after RCBI (12% ODSH vs. 41% VEH; n=22, p<0.05). Furthermore, ODSH did not affect water consumption or body mass accrual after RI or RCBI. ODSH was not able to counteract the negative alterations in hematology, splenocytes, or bone marrow cell counts after RI or RCBI. These data illustrate that ODSH in combination with antibiotic treatments, may not be a mitigating countermeasure for RCBI.