BACKGROUND Data on antimicrobial prophylaxis for open fractures is limited, with many protocols based on expert recommendations. These protocols include aminoglycosides (AGs) for fractures with significant soft tissue injury, but these drugs are associated with acute kidney injury (AKI) in other settings; this risk has not been defined for open fracture prophylaxis. METHODS We performed a retrospective study from May 2012 to October 2014 at our Level 1 trauma center. Patients with open fractures were evaluated for demographics, location/type of fracture, injury severity, and receipt of an AG. Outcomes included rates of AKI, infection, and mortality. RESULTS There were 167 patients with open fractures during the study period (119 males, mean age 42 ± 17 [standard deviation] years), with 80 (48%) receiving prophylactic gentamicin (AG+ group). The AG+ and AG- patients had similar fracture sites and Injury Severity Scores (ISSs) (12.6 ± 9.9 AG+ vs. 15.9 ± 13.2 AG-) but were more likely to have sustained blunt trauma (96% AG+ vs. 77%; p < 0.001) or received intravenous contrast medium ≤48 h from admission (75% AG+ vs. 56% AG-; p = 0.01). Gentamicin was not associated with AKI (odds ratio [OR] 0.22; 95% confidence interval [CI] 0.020-2.44; p = 0.22), whereas hypotension on admission (OR 10.7; 95% CI 1.42-80.93; p = 0.02) and ISS (OR 1.1; 95% CI 1.01-1.20; p = 0.02) were both associated with AKI. Only four fracture site infections were identified, three in the AG+ group and one in the AG- group (3.8% vs. 1.1%; p = 0.27). The mortality rate was greater in the AG- group (3.8% vs. 12.6%; p = 0.04). CONCLUSIONS Prophylactic gentamicin is not associated with AKI, whereas hypotension on admission and higher ISS were. The use of nephrotoxic agents, including aminoglycosides, should be restricted in open fracture patients presenting with hypotension or a high ISS.